- Email: [email protected]
Immune biomarkers of anti-EGFR monoclonal antibody therapy
reviews
Annals of Oncology Annals of Oncology 26: 40–47, 2015 doi:10.1093/annonc/mdu156 Published online 4 July 2014
Immune biomarkers of anti-EGFR monoclonal antibody therapy S. Trivedi1, F. Concha-Benavente2, R. M. Srivastava1, H. B. Jie1, S. P. Gibson1, N. C. Schmitt1 & R. L. Ferris1,2,3* 1
Department of Otolaryngology, University of Pittsburgh School of Medicine; 2Department of Immunology, University of Pittsburgh; 3Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, USA
Received 22 November 2013; revised 8 April 2014; accepted 9 April 2014
introduction The epidermal growth factor receptor (EGFR) is a member of the ErbB family of four structurally related receptor tyrosine kinases [1]. These transmembrane proteins are composed of an extracellular domain for binding of specific ligands, and an intracellular domain with tyrosine kinase activity. Ligand binding causes dimerization of the receptor which triggers a signaling cascade that promotes cell survival and tissue invasion, while inhibiting apoptosis [2]. EFGR is frequently overexpressed in epithelial malignancies, which corresponds to a decrease in patient survival, providing a target for tumor antigen (TA)-targeted monoclonal antibody (mAb)-based immunotherapy. Cetuximab and panitumumab are two such mAbs which have been incorporated to treatment regimens for colorectal and head and neck cancers [3–11]. As single agents, these antibodies confer clinical responses in 10%–15% of patients with advanced untreated and recurrent metastatic disease [12]. Interestingly, when used in combination with chemotherapy or radiotherapy, the efficacy of these mAbs is often improved with higher response rates, prolonged duration of response and crucially, prolonged patient survival [13, 14].
*Correspondence to: Dr Robert L. Ferris, Cancer Immunology Program, University of Pittsburgh Cancer Institute, 5117 Centre Ave, Suite 2.26b, Pittsburgh, PA 15213, USA. Tel: +1-412-647-4654; E-mail: [email protected]
Although these antibodies gave new hope to those with advanced, therapy-resistant disease, the subpopulation of patients who successfully respond to treatment remains low [15–22]. Cetuximab, the first anti-EGFR mAb to receive regulatory approval, has been extensively studied and, here, we reviewed the immunogenic mechanisms that underlie the antitumor effect of cetuximab and, to some extent, panitumumab, distinguishing these two mAbs clinically and biologically, as well as detailing some of the newer anti-EGFR mAbs currently in the clinical trial stages.
the immunological aspect of anti-EGFR monoclonal antibodies Cetuximab is a murine-human chimeric antibody composed of the variable region of a murine anti-EGFR antibody joined with human IgG1 heavy and light chain regions, which binds to the extracellular domain of the EGF receptor with a twofold greater affinity than its natural ligands EGF and transforming growth factor-α [23–25]. In addition to its role in colorectal carcinoma (CRC), cetuximab is approved by both the FDA and the European Medicines Agency (EMA) for treatment of locally advanced untreated squamous cell carcinoma of the head and neck (SCCHN) in combination with chemoradiotherapy and as a single agent for metastatic or recurrent disease. Binding of cetuximab to the EGFR results in competitive inhibition of
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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The tumor antigen (TA)-targeted monoclonal antibodies (mAb) cetuximab and panitumumab target the human epidermal growth factor receptor and have been integrated into treatment regimens for advanced squamous cell carcinoma of the head and neck (SCCHN). The therapeutic efficacy of these mAbs has been found to be enhanced when combined with radiotherapy and chemotherapy. However, clinical trials indicate that these findings are limited to fewer than 20% of treated patients. Therefore, identifying patients who are likely to benefit from these agents is crucial to improving therapeutic strategies. Interestingly, it has been noted that TA-targeted mAbs mediate their effects by contributing to cell-mediated cytotoxicity in addition to inhibition of downstream signaling pathways. Here, we describe the potential immunogenic mechanisms underlying these clinical findings, their role in the varied clinical response and identify the putative biomarkers of antitumor activity. We review potential immunological biomarkers that affect mAb therapy in SCCHN patients, the implications of these findings and how they translate to the clinical scenario, which are critical to improving patient selection and ultimately outcomes for patients undergoing therapy. Key words: EGFR, immune biomarkers, monoclonal antibodies, head and neck cancer
reviews
Annals of Oncology
has a significant role to play in their effectiveness [34]. Cetuximab treatment of SCCHN cells in vitro does not result in apoptosis or lysis of tumor cells; [20] this only occurs in the presence of lymphocytes, supporting an immune-mediated mechanism contributing to the antitumor effect of anti-EGFR mAb therapy. ADCC is a lytic reaction characterized by cetuximab and panitumumab coating EGFR on the surface of tumor cells and binding to FcγRs expressed on immune effector cells, activating them and resulting in lysis of the antibody-coated target cells (Figure 1). Cetuximab-mediated ADCC reactions can be enhanced by cytokines, including interleukin 12 (IL-12), interleukin 2 and other NK cell-activating cytokines thus indicating the importance of NK cell function in effective ADCC reactions. Studies in both breast cancer and SCCHN indicate that cytokine activation of NK cells results in enhanced NK cell lytic activity against cetuximab-coated cells as well as increased antitumor effects mediated by these activated NK cells [35, 36]. Three classes of FcγR encoded by eight genes have been identified in humans, FcγRI (CD64), FcγRII (CD32), and FcγRIII (CD16a). Some FcγR display allelic polymorphisms which generate allotypes that have been reported to be functionally relevant in the ADCC mechanism [21]. A clinically relevant example of this is seen in the gene encoding FcγRIIIa, where a single-nucleotide substitution at position 158 results in the substitution of phenylalanine (F) by valine (V) in the IgG-binding domain, which results in varying patient response to cetuximab treatment [16]. Unlike in CRC where better clinical response to cetuximab therapy has been shown to correlate with the FcγRIIIa VV or FF genotypes [16, 22, 37], in vitro studies in SCCHN appear to indicate a correlation with the FcγRIIIa VV genotype and more potent ADCC [21, 38]. Clinical data are not yet available from cetuximab clinical trials but a retrospective cohort showed a nonsignificant association with the V-encoding allele. Interestingly, this phenomenon is also reported in patients treated with the
Fc-gamma receptor polymorphisms and clinical response Although anti-EGFR mAbs inhibit EGFR tyrosine phosphorylation and subsequent downstream signaling, evidence suggests that triggering of ADCC mediated by mAb-activated NK cells
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Tumor cell Figure 1. Antibody-dependent, cell-mediated cytotoxicity (ADCC). ADCC mediated by tumor antigen (TA)-targeted monoclonal antibodies (mAbs) in the tumor microenvironment. TA-positive tumor cells are exposed to TA-targeted mAbs which leads to opsonization through binding of cetuximab and panitumumab to the TA epitopes expressed on tumor targets. NK cell recognition of opsonized tumor cells is mediated via Fcgamma receptor (FcγR) III/CD16 while FcγRIIa/CD32 mediates recognition. This effect is diminished by regulatory T cells (Treg) which exert a suppressive function on effector immune cells through secretion of interleukin 10, transforming growth factor-β and adenosine into the tumor microenvironment.
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ligand binding and receptor phosphorylation as well as associated downstream signaling while concomitantly inducing receptor downregulation through dimerization and internalization [26]. The three main pathways downstream of EGFR are the MAPK, PI3K/AKT and JAK/signal transducer and activator of transcription (STAT) pathways [27–29]. However, in addition to inhibition of these mitogenic pathways, the effects of cetuximab therapy may also be mediated by antibody-dependent, cellmediated cytotoxicity (ADCC) [30], complement-mediated cytotoxicity [15] and adaptive immunity-mediated by CD8+ cytotoxic T lymphocytes (CTL) [31]. Panitumumab is a fully human IgG2 mAb which also targets the extracellular domain of EGFR. It binds the EGFR with great affinity (Kd = 1.33 ± 0.29 nmol/l) and was developed with the intention of causing fewer hypersensitivity reactions than cetuximab [32]. However, as an IgG2 isotype, it has lower immunogenicity potential, through poor Fc-gamma receptor (FcγR) binding [16]. Approved by both the FDA and EMA for use in CRC, panitumumab has not yet been approved for use in SCCHN although several clinical trials are reported or currently underway [33]. In addition to receptor downregulation and inhibition of downstream signaling of the EGFR, the clinical efficacy of panitumumab is believed to be mediated by induction of cell cycle arrest and inhibition of angiogenesis [17, 18], as well as facilitating ADCC, potentially through FcγRIIa on neutrophils [19] although to a lesser degree than cetuximab therapy.
reviews HER2-specific mAb trastuzumab for breast cancer [39, 40]. Our in vivo studies seem to indicate that FcγRIIIa genotype is not associated with disease-specific survival in a retrospective cohort of 107 cetuximab-treated patients with SCCHN [31]. As yet, no prospectively collected clinical data in SCCHN have been published confirming genotype as a useful biomarker of clinical activity.
modulation of the human leukocyte antigen class I and antigen-processing machinery expression by EGFR-specific mAb
| Trivedi et al.
signal transducer and activator of transcription 3 as a mechanism for SCCHN immune escape EGFR overexpression in SCCHN cells induces the constitutive activation of STAT3, a known oncogenic transcription factor which results in tumor growth [60–63], and immunosuppression [52, 55]. Other receptors from the ErbB/HER family can also be ligated by their tumor-overexpressed ligands causing EGFR-independent STAT3 activation in an autocrine or paracrine fashion. Notably, the interleukin 6 (IL-6) receptor (IL-6R)/CD130 signaling complex has also been shown to be a major pathway involved in EGFR-independent STAT3 activation and tumorigenesis [64–66]; indeed, it is overexpressed in SCCHN cells and its detection is correlated with poor survival in SCCHN patients [67]. Thus, the expected cetuximabmediated growth inhibition of SCCHN via blocking EGFRdependent survival signals may not be fully effective, since STAT3 constitutive activation takes place through alternative pathways, such as IL-6/gp130. SCCHN cells exhibit a constitutively active STAT3 that blocks apoptosis and induces proliferation, angiogenesis and immune evasion [68, 69]. STAT3 is considered an oncogene and its inhibition leads to apoptosis in vitro and to an impaired tumor growth in xenografted mouse models [70, 71]. STAT3 plays a major role in promoting tumor immune evasion. Previous work shows that it not only inhibits production of inflammatory signals from tumor cells, but also production of immunosuppressive mediators, thus inducing a tolerant tumor microenvironment [72, 73]. Due to this situation, SCCHN cells may evade cetuximab-dependent immune effector cell tumor cytolysis, as well as EGFR signaling inhibition, through mechanisms discussed below and shown in Figure 2. EGFR-mediated STAT3 activation induces the expression of vascular endothelial growth factor (VEGF), IL-6 and interleukin 10 (IL-10) in many tumors including melanoma [64, 67]. Increased levels of VEGF have been found to induce tumor growth, metastasis and resistance to treatment in SCCHN [74, 75]. In a recent phase II clinical trial, the addition of bevacizumab (a humanized anti-VEGF-A IgG1 mAb) with cetuximab therapy was shown to induce a 16% clinical response rate in 46 patients with recurrent or metastatic SCCHN [76], suggesting a potential role for combination therapy, though further studies are needed to validate these findings. IL-6, IL-10 and VEGF are known to activate STAT3 in tumor-associated immune cells, providing a feed-forward mechanism to ensure a STAT3-dominated tumor permissive microenvironment. Tumor-secreted transforming growth factor-β (TGF-β), VEGF and IL-10 induce T-cell tolerance through inhibition of dendritic cell (DC) differentiation and maturation [77, 78]. Moreover, blocking STAT3 in macrophages-induced restoration of T-cell responsiveness by restoring the secretion of IL12 and CCL5. Likewise, IL-10 protects tumor cells from CTL lysis by downregulation of APM components (TAP1, TAP2) and surface HLA class I expression [79, 80]. Thus, immunosuppressive cytokines induced by EGFR-JAK2-STAT3 activation, potentially inhibited by EGFR-targeted mAb, may serve as biomarkers of response to anti-EGFR therapy.
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Anti-EGFR mAb therapy is associated with proinflammatory side-effects, the most common of which is the development of a characteristic skin rash [41, 42] suggesting that EGFR signaling is involved in the control of immunoregulatory genes. Interestingly, the skin rash may correlate with improved response to therapy and better clinical outcome for cetuximab-treated patients [43]. Overexpression of EGFR associated with SCCHN has been shown to repress expression of the human leukocyte antigen (HLA) class I and antigen-processing machinery (APM) components [44–47], a phenomenon associated with tumor cell escapes from CTL recognition and lysis [48]. The process of tagging endogenous proteins for degradation and processing before formation of the HLA class I–peptide complexes to be presented on the cell surface involves the cooperation of multiple components within the APM of antigen-presenting cells. These HLA class I– peptide complexes are then recognized by T cells expressing the corresponding T-cell receptors. The resulting impaired tumor antigen (TA) processing and presentation leads to poor recognition of tumor cells by CTL and the development of an immune escape phenotype that correlates with poor clinical outcome [48– 51]. Although the exact molecular mechanisms for this remain under investigation [52], these effects appear to be ameliorated by anti-EGFR antibody therapy [53]. Cetuximab has been shown to upregulate HLA class I antigens on the level of gene transcription and correlates with increased cutaneous expression of HLA class I and II proteins in patients who developed skin rash upon cetuximab therapy [44]. The cytokines and molecular signals that regulate the finely tuned APM are often disrupted in SCCHN [49, 54]. One such molecular signal is the transcription factor STAT1. The activated form of STAT1, phospho-STAT1 (pSTAT1) and has been shown to be necessary for APM expression and subsequent T-cell recognition [55, 56]. The characteristic low basal pSTAT1 level which is seen in SCCHN has been attributed to Src homology-2 domain-containing phosphatase (SHP2), a known negative regulator of the JAK-STAT1 signal transduction pathway, which is frequently overexpressed in multiple malignancies [52, 57, 58]. While overexpression of EGFR has not been shown to be correlated with SHP2 increase in SCCHN, in other malignancies, such as lung cancer, activating mutations of EGFR have been linked to activation of SHP2 [59]. Studies are currently underway in SCCHN to investigate the role that EGFR signaling downregulation by anti-EGFR mAb may have in inhibiting SHP2 and subsequent increase in pSTAT1, which has been shown to restore antitumor immunity in the tumor microenvironment.
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Figure 2. Signal transducer and activator of transcription 3 (STAT3) pathways involved in immune escape. epidermal growth factor receptor (EGFR) overexpression noted in squamous cell carcinoma of the head and neck results in constitutive STAT3 activation through the JAK/STAT pathway. STAT3 is a known oncogenic transcription factor which results in tumor growth and immune suppression, in part due to the induction of immunosuppressive cytokines such as interleukin 6 (IL-6), vascular endothelial growth factor (VEGF) and interleukin 10 (IL-10). The IL-6R/CD130 signaling complex, also upregulated in squamous cell carcinoma of the head and neck, is a major pathway in EGFR-independent STAT3 activation and may contribute to the modest response seen in therapy with EGFR-blocking antibodies. Interferon-γ (IFN-γ) activates STAT1 phosphorylation which opposes the action of STAT3, EGFR overexpression activates SHP2 which conversely inhibits the phosphorylation of STAT1.
HPV status In the USA and Northern Europe, the incidence rate of some oropharyngeal cancers, particularly those of the tonsil and tongue base have steadily increased since the 1970s. This is especially noted in younger patients without the usual recognized risk factors for SCCHN [81–83]. Along with other etiological factors, the primary cause for this has been attributed to persistent infection with high-risk human papillomavirus (HPV) [84, 85]. Tumors that are positive for HPV have a different biology and phenotypical features than HPV-negative tumors. They tend to be poorly differentiated with scant keratinization [86]. The difference in HPV-positive and -negative cancers is noted in prognostic outcomes for the patient, with HPV-positive disease being exquisitely radiosensitive and therefore having more favorable clinical outcomes than patients with smoking-related SCCHN [87, 88]. Results of a multicenter, randomized phase III trial by the Radiation Therapy Oncology Group (RTOG) looking at concurrent radiation and cisplatin versus concurrent radiation, cisplatin and cetuximab for stage III and IV SCCHN suggested that patients with HPV-positive tumors may not benefit from
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addition of cetuximab therapy to cisplatin. An ongoing RTOG trial 1016 aims to evaluate the impact of EGFR-specific mAb, cetuximab versus cisplatin in the context of HPV + disease. A similar phase III SPECTRUM trial that looked at the safety and efficacy of panitumumab in recurrent or metastatic SCCHN found that Panitumumab plus cisplatin improved both overall survival (OS) and progression-free survival (PFS) in HPV-positive tumors, and showed no incremental benefit in patients with HPV-negative tumors. HPV status was classified differently in the RTOG and SPECTRUM trials, clouding the interpretation of these results. Further studies are warranted to delineate the role of HPV status as a potential immune biomarker of anti-EGFR monoclonal antibody therapy.
regulatory T cells and tumor-associated macrophages EGFR-specific CTL have been identified in SCCHN patients but not in healthy donors suggesting that EGFR may function as an immunogenic TA in cancer patients [89]. During therapy with
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Increased antigen presentation
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newer EGFR-specific mAb Several novel anti-EGFR antibodies have recently been brought to the market, although none are currently approved for use against SCCHN within the USA, there are currently ongoing clinical trials underway to investigate their efficacy. Zalutumumab is a fully human IgG1 mAb, which was tested as a second-line agent in a recent phase III randomized clinical trial of 286 patients with recurrent or metastatic disease refractory to platinum-based therapy. SCCHN patients who received zalutumumab with supportive care versus supportive care alone demonstrated no statistically significant improvement in OS between either group. Of note however, the PFS appeared longer
| Trivedi et al.
in the zalutumumab-treated group compared with supportive therapy alone [102]. Nimotuzumab is a humanized IgG1 mAb currently approved for use in the management of SCCHN in countries outside the USA and Europe. A potential advantage of nimotuzumab is its lower immunogenic side-effects profile [103]. Initial phase I studies revealed an absence or mild skin toxicity and hypersensitivity reactions [104].
summary Immune therapy continues to be an evolving area of cancer therapy, in order to better evaluate patient response to therapy, certain immune biomarkers should be identified and monitored; here, we have described the potential immune biomarkers of cetuximab and panitumumab therapy. Although the importance of FcγR polymorphisms in the ADCC reaction has been noted in the breast cancer and CRC models, it is yet to be seen whether it is a useful biomarker in the setting of SCCHN. In vitro studies indicate a correlation with the FcγRIIIa VV genotype and more potent ADCC reactions; however, this finding did not appear to correlate with disease-specific survival in a large retrospective study involving cetuximab and SCCHN. Future prospective cohorts must be interrogated. Constitutive STAT3 activation seen in SCCHN promotes tumor immune evasion, and contributes to induction of a tolerant tumor microenvironment. Additionally, it mediates expression of cytokines and growth factors known to promote tumorigenesis and correlates with poor clinical outcomes, an effect that may take place through alternative, EGFR-independent pathways. Clinical trials looking at combining EGFR blockade as well as blockade of pathways downstream of STAT3 may indicate a role for STAT3 or TGF-β modulation in successful immunotherapy. The identification of EGFR-specific CTL in SCCHN patients, which increase in frequency during treatment with TA-targeted mAbs suggests that EGFR may function as an immunogenic protein in these patients, and that cetuximab may drive NK: DC priming of cellular immunity. However, the strong suppressive function of Treg populations in the circulation of these patients may be responsible for the lack of antitumor effects seen with despite this elevated frequency of EGFR-specific CTL in SCCHN patients. The suppressive functions of Tregs are mediated primarily through TGF-β and IL-10 which can be additionally be secreted by Tregs in a STAT3-dependent fashion, further propagating the immunosuppressive signals. As the field of TA-targeted mAb-based immunotherapy continues to expand, a greater understanding of the immunogenic mechanisms that underlie their antitumor effect is necessary. Future mAb trials should monitor immune biomarkers and correlate these with patient response.
funding This review was supported in part by National Institutes of Health grants P30CA047904, P50CA097190 and R01DE19727.
disclosure RLF has received research funding from Bristol-Myers Squibb and Amgen. He has served as a consultant to Bristol-Myers
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anti-EGFR mAbs there is an observed enhancement of EGFRspecific CTL frequencies, the generation of these CTL appears to be initiated by cetuximab-induced NK cell activation [31, 90]. Despite the elevated frequency of EGFR-specific CTL in SCCHN patients, it was noted that these CTL did not sufficiently inhibit tumor growth. One explanation for finding has been proposed to be due to is elevated levels of suppressive regulatory T-cell (Treg) populations in the circulation and tumor sites of these patients. Tregs possess a strong suppressive function, through TGF-β, IL10 and adenosine produced by the ecto-enzymes CD39 and CD73, and are believed to result from chronically activated T cells [91]. CD25+CD4+ Treg cells constitutively express the transcription factor Foxp3 and regulate immune self-tolerance by suppressing aberrant or excessive immune responses which may be harmful to the host. Abnormalities in Treg function are seen in many autoimmune and inflammatory diseases [92, 93]. Within the tumor microenvironment, it is believed that the development of Tregs results from chronic exposure of T cells to selfantigens, including EGFR. Therefore, although CD8+ T cells are present in some SCCHN patients, their antitumor activity may be suppressed by Tregs [94] (Jie HB, in press). Anti-EGFR mAb therapy significantly increases both the frequency of EGFR-specific TIL and Tregs in both the circulation and tumor sites of patients with SCCHN. Several additional cytokine interactions are involved in generation of Tregs in SCCHN patients. TGF-β, a known immunosuppressive cytokine, is found to be present at high concentrations in plasma of cancer patients and is associated with disease progression and poor response to immunotherapy. TGF-β production is characteristic of many malignancies including melanoma, breast and colon cancer and is known to prevent proper CTL generation and function [95]; however, TGF-β secretion by SCCHN is still not well characterized. Interestingly, TGFβ is involved in the generation of Tregs that are known to inhibit CD8+ T-cell activation, interferon-γ production and proliferation [96]. Additionally, Tregs can secret TGF-β and IL-10 in a STAT3-dependent fashion further propagating the immunosuppressive signals [97, 98]. This intricate tumor cellular network also includes TAMs, which are induced by monocyte exposure to tumor-secreted IL-6, IL-10 and VEGF [99]. TAMs suppress DC maturation in an IL-10-dependent manner that in turn inhibits CD8+ T-cell proliferation and function [100, 101]. TAM-derived IL-10 can also induce differentiation of naive T cells into Tregs [98], and thus may suppress mAb-induced cellular immunity in the tumor microenvironment.
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Squibb, and VentiRx. All remaining authors have declared no conflicts of interest.
references
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23. Gill GN, Kawamoto T, Cochet C et al. Monoclonal anti-epidermal growth factor receptor antibodies which are inhibitors of epidermal growth factor binding and antagonists of epidermal growth factor binding and antagonists of epidermal growth factor-stimulated tyrosine protein kinase activity. J Biol Chem 1984; 259: 7755–7760. 24. Goldstein NI, Prewett M, Zuklys K et al. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res 1995; 1: 1311–1318. 25. Kim ES, Khuri FR, Herbst RS. Epidermal growth factor receptor biology (IMCC225). Curr Opin Oncol 2001; 13: 506–513. 26. Sharafinski ME, Ferris RL, Ferrone S et al. Epidermal growth factor receptor targeted therapy of squamous cell carcinoma of the head and neck. Head Neck 2010; 32: 1412–1421. 27. Kruger JS, Reddy KB. Distinct mechanisms mediate the initial and sustained phases of cell migration in epidermal growth factor receptor-overexpressing cells. Mol Cancer Res 2003; 1: 801–809. 28. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002; 2: 489–501. 29. Ellerbroek SM, Halbleib JM, Benavidez M et al. Phosphatidylinositol 3-kinase activity in epidermal growth factor-stimulated matrix metalloproteinase-9 production and cell surface association. Cancer Res 2001; 61: 1855–1861. 30. Bleeker WK, Lammerts van Bueren JJ, van Ojik HH et al. Dual mode of action of a human anti-epidermal growth factor receptor monoclonal antibody for cancer therapy. J Immunol 2004; 173: 4699–4707. 31. Srivastava RM, Lee SC, Andrade Filho PA et al. Cetuximab-activated natural killer and dendritic cells collaborate to trigger tumor antigen-specific T-cell immunity in head and neck cancer patients. Clin Cancer Res 2013; 19: 1858–1872. 32. Yang XD, Jia XC, Corvalan JR et al. Development of ABX-EGF, a fully human antiEGF receptor monoclonal antibody, for cancer therapy. Crit Rev Oncol Hematol 2001; 38: 17–23. 33. Vermorken JB, Stohlmacher-Williams J, Davidenko I et al. Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial. Lancet Oncol 2013; 14: 697–710. 34. Ferris RL, Jaffee EM, Ferrone S. Tumor antigen-targeted, monoclonal antibodybased immunotherapy: clinical response, cellular immunity, and immunoescape. J Clin Oncol 2010; 28: 4390–4399. 35. Luedke E, Jaime-Ramirez AC, Bhave N et al. Cetuximab therapy in head and neck cancer: immune modulation with interleukin-12 and other natural killer cellactivating cytokines. Surgery 2012; 152: 431–440. 36. Roda JM, Joshi T, Butchar JP et al. The activation of natural killer cell effector functions by cetuximab-coated, epidermal growth factor receptor positive tumor cells is enhanced by cytokines. Clin Cancer Res 2007; 13: 6419–6428. 37. Pander J, Gelderblom H, Antonini NF et al. Correlation of FCGR3A and EGFR germline polymorphisms with the efficacy of cetuximab in KRAS wild-type metastatic colorectal cancer. Eur J Cancer 2010; 46: 1829–1834. 38. Taylor RJ, Chan SL, Wood A et al. FcgammaRIIIa polymorphisms and cetuximab induced cytotoxicity in squamous cell carcinoma of the head and neck. Cancer Immunol Immunother 2009; 58: 997–1006. 39. Musolino A, Naldi N, Bortesi B et al. Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J Clin Oncol 2008; 26: 1789–1796. 40. Tamura K, Shimizu C, Hojo T et al. FcgammaR2A and 3A polymorphisms predict clinical outcome of trastuzumab in both neoadjuvant and metastatic settings in patients with HER2-positive breast cancer. Ann Oncol 2011; 22: 1302–1307. 41. Li T, Perez-Soler R. Skin toxicities associated with epidermal growth factor receptor inhibitors. Target Oncol 2009; 4: 107–119. 42. Abdullah SE, Haigentz M, Jr, Piperdi B. Dermatologic toxicities from monoclonal antibodies and tyrosine kinase inhibitors against EGFR: pathophysiology and management. Chemother Res Pract 2012; 2012: 351210. 43. Perez-Soler R, Saltz L. Cutaneous adverse effects with HER1/EGFR-targeted agents: is there a silver lining? J Clin Oncol 2005; 23: 5235–5246. 44. Pollack BP, Sapkota B, Cartee TV. Epidermal growth factor receptor inhibition augments the expression of MHC class I and II genes. Clin Cancer Res 2011; 17: 4400–4413.
doi:10.1093/annonc/mdu156 |
Downloaded from http://annonc.oxfordjournals.org/ at Sussex Language Institute on July 28, 2015
1. Bublil EM, Yarden Y. The EGF receptor family: spearheading a merger of signaling and therapeutics. Curr Opin Cell Biol 2007; 19: 124–134. 2. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001; 2: 127–137. 3. Langer CJ. Targeted therapy in head and neck cancer: state of the art 2007 and review of clinical applications. Cancer 2008; 112: 2635–2645. 4. Blick SK, Scott LJ. Cetuximab: a review of its use in squamous cell carcinoma of the head and neck and metastatic colorectal cancer. Drugs 2007; 67: 2585–2607. 5. Frampton JE. Cetuximab: a review of its use in squamous cell carcinoma of the head and neck. Drugs 2010; 70: 1987–2010. 6. Bourhis J, Lefebvre JL, Vermorken JB. Cetuximab in the management of locoregionally advanced head and neck cancer: expanding the treatment options? Eur J Cancer 2010; 46: 1979–1989. 7. Cripps C, Winquist E, Devries MC et al. Epidermal growth factor receptor targeted therapy in stages III and IV head and neck cancer. Curr Oncol 2010; 17: 37–48. 8. Holubec L, Liska V, Matejka VM et al. The role of cetuximab in the treatment of metastatic colorectal cancer. Anticancer Res 2012; 32: 4007–4011. 9. Spiro H. Cetuximab for metastatic colorectal cancer. N Engl J Med 2009; 361: 95; author reply 96–97. 10. Amado RG, Wolf M, Peeters M et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008; 26: 1626–1634. 11. Noguchi T, Ritter G, Nishikawa H. Antibody-based therapy in colorectal cancer. Immunotherapy 2013; 5: 533–545. 12. Adams GP, Weiner LM. Monoclonal antibody therapy of cancer. Nat Biotechnol 2005; 23: 1147–1157. 13. Bonner JA, Harari PM, Giralt J et al. Radiotherapy plus cetuximab for squamouscell carcinoma of the head and neck. N Engl J Med 2006; 354: 567–578. 14. Cunningham D, Humblet Y, Siena S et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004; 351: 337–345. 15. Dechant M, Weisner W, Berger S et al. Complement-dependent tumor cell lysis triggered by combinations of epidermal growth factor receptor antibodies. Cancer Res 2008; 68: 4998–5003. 16. Bibeau F, Lopez-Crapez E, Di Fiore F et al. Impact of Fc{gamma}RIIa-Fc{gamma} RIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with cetuximab plus irinotecan. J Clin Oncol 2009; 27: 1122–1129. 17. Foon KA, Yang XD, Weiner LM et al. Preclinical and clinical evaluations of ABXEGF, a fully human anti-epidermal growth factor receptor antibody. Int J Radiat Oncol Biol Phys 2004; 58: 984–990. 18. Lynch DH, Yang XD. Therapeutic potential of ABX-EGF: a fully human antiepidermal growth factor receptor monoclonal antibody for cancer treatment. Semin Oncol 2002; 29: 47–50. 19. Schneider-Merck T, Lammerts van Bueren JJ, Berger S et al. Human IgG2 antibodies against epidermal growth factor receptor effectively trigger antibodydependent cellular cytotoxicity but, in contrast to IgG1, only by cells of myeloid lineage. J Immunol 2010; 184: 512–520. 20. Lopez-Albaitero A, Ferris RL. Immune activation by epidermal growth factor receptor specific monoclonal antibody therapy for head and neck cancer. Arch Otolaryngol Head Neck Surg 2007; 133: 1277–1281. 21. Lopez-Albaitero A, Lee SC, Morgan S et al. Role of polymorphic Fc gamma receptor IIIa and EGFR expression level in cetuximab mediated, NK cell dependent in vitro cytotoxicity of head and neck squamous cell carcinoma cells. Cancer Immunol Immunother 2009; 58: 1853–1864. 22. Zhang W, Gordon M, Schultheis AM et al. FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab. J Clin Oncol 2007; 25: 3712–3718.
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66. Gao SP, Mark KG, Leslie K et al. Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J Clin Invest 2007; 117: 3846–3856. 67. Duffy SA, Taylor JM, Terrell JE et al. Interleukin-6 predicts recurrence and survival among head and neck cancer patients. Cancer 2008; 113: 750–757. 68. Leeman RJ, Lui VW, Grandis JR. STAT3 as a therapeutic target in head and neck cancer. Expert Opin Biol Ther 2006; 6: 231–241. 69. Regis G, Pensa S, Boselli D et al. Ups and downs: the STAT1:STAT3 seesaw of Interferon and gp130 receptor signalling. Semin Cell Dev Biol 2008; 19: 351–359. 70. Fletcher S, Drewry JA, Shahani VM et al. Molecular disruption of oncogenic signal transducer and activator of transcription 3 (STAT3) protein. Biochem Cell Biol 2009; 87: 825–833. 71. Zhang X, Zhang J, Wang L et al. Therapeutic effects of STAT3 decoy oligodeoxynucleotide on human lung cancer in xenograft mice. BMC Cancer 2007; 7: 149. 72. Wang T, Niu G, Kortylewski M et al. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med 2004; 10: 48–54. 73. Kortylewski M, Kujawski M, Wang T et al. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med 2005; 11: 1314–1321. 74. Smith BD, Smith GL, Carter D et al. Prognostic significance of vascular endothelial growth factor protein levels in oral and oropharyngeal squamous cell carcinoma. J Clin Oncol 2000; 18: 2046–2052. 75. Riedel F, Gotte K, Schwalb J et al. Serum levels of vascular endothelial growth factor in patients with head and neck cancer. Eur Arch Otorhinolaryngol 2000; 257: 332–336. 76. Argiris A, Kotsakis AP, Hoang T et al. Cetuximab and bevacizumab: preclinical data and phase II trial in recurrent or metastatic squamous cell carcinoma of the head and neck. Ann Oncol 2013; 24: 220–225. 77. Gabrilovich DI, Chen HL, Girgis KR et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 1996; 2: 1096–1103. 78. Yang AS, Lattime EC. Tumor-induced interleukin 10 suppresses the ability of splenic dendritic cells to stimulate CD4 and CD8 T-cell responses. Cancer Res 2003; 63: 2150–2157. 79. Yue FY, Dummer R, Geertsen R et al. Interleukin-10 is a growth factor for human melanoma cells and down-regulates HLA class-I, HLA class-II and ICAM-1 molecules. Int J Cancer 1997; 71: 630–637. 80. Salazar-Onfray F, Charo J, Petersson M et al. Down-regulation of the expression and function of the transporter associated with antigen processing in murine tumor cell lines expressing IL-10. J Immunol 1997; 159: 3195–3202. 81. Shiboski CH, Schmidt BL, Jordan RC. Tongue and tonsil carcinoma: increasing trends in the U.S. population ages 20–44 years. Cancer 2005; 103: 1843–1849. 82. Conway DI, Stockton DL, Warnakulasuriya KA et al. Incidence of oral and oropharyngeal cancer in United Kingdom (1990–1999)—recent trends and regional variation. Oral Oncol 2006; 42: 586–592. 83. Hammarstedt L, Dahlstrand H, Lindquist D et al. The incidence of tonsillar cancer in Sweden is increasing. Acta Otolaryngol 2007; 127: 988–992. 84. Ramqvist T, Dalianis T. An epidemic of oropharyngeal squamous cell carcinoma (OSCC) due to human papillomavirus (HPV) infection and aspects of treatment and prevention. Anticancer Res 2011; 31: 1515–1519. 85. Marur S, D’Souza G, Westra WH et al. HPV-associated head and neck cancer: a virus-related cancer epidemic. Lancet Oncol 2010; 11: 781–789. 86. Wilczynski SP, Lin BT, Xie Y et al. Detection of human papillomavirus DNA and oncoprotein overexpression are associated with distinct morphological patterns of tonsillar squamous cell carcinoma. Am J Pathol 1998; 152: 145–156. 87. Furniss CS, McClean MD, Smith JF et al. Human papillomavirus 16 and head and neck squamous cell carcinoma. Int J Cancer 2007; 120: 2386–2392. 88. Fakhry C, Gillison ML. Clinical implications of human papillomavirus in head and neck cancers. J Clin Oncol 2006; 24: 2606–2611. 89. Hoffmann TK, Schirlau K, Sonkoly E et al. A novel mechanism for anti-EGFR antibody action involves chemokine-mediated leukocyte infiltration. Int J Cancer 2009; 124: 2589–2596.
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45. Bandoh N, Ogino T, Katayama A et al. HLA class I antigen and transporter associated with antigen processing downregulation in metastatic lesions of head and neck squamous cell carcinoma as a marker of poor prognosis. Oncol Rep 2010; 23: 933–939. 46. Ogino T, Bandoh N, Hayashi T et al. Association of tapasin and HLA class I antigen down-regulation in primary maxillary sinus squamous cell carcinoma lesions with reduced survival of patients. Clin Cancer Res 2003; 9: 4043–4051. 47. Ogino T, Shigyo H, Ishii H et al. HLA class I antigen down-regulation in primary laryngeal squamous cell carcinoma lesions as a poor prognostic marker. Cancer Res 2006; 66: 9281–9289. 48. Lopez-Albaitero A, Nayak JV, Ogino T et al. Role of antigen-processing machinery in the in vitro resistance of squamous cell carcinoma of the head and neck cells to recognition by CTL. J Immunol 2006; 176: 3402–3409. 49. Meissner M, Reichert TE, Kunkel M et al. Defects in the human leukocyte antigen class I antigen processing machinery in head and neck squamous cell carcinoma: association with clinical outcome. Clin Cancer Res 2005; 11: 2552–2560. 50. Ferris RL, Hunt JL, Ferrone S. Human leukocyte antigen (HLA) class I defects in head and neck cancer: molecular mechanisms and clinical significance. Immunol Res 2005; 33: 113–133. 51. Ferris RL, Whiteside TL, Ferrone S. Immune escape associated with functional defects in antigen-processing machinery in head and neck cancer. Clin Cancer Res 2006; 12: 3890–3895. 52. Leibowitz MS, Srivastava RM, Andrade Filho PA et al. SHP2 is overexpressed and inhibits pSTAT1-mediated APM component expression, T-cell attracting chemokine secretion, and CTL recognition in head and neck cancer cells. Clin Cancer Res 2013; 19: 798–808. 53. Pollack BP. EGFR inhibitors, MHC expression and immune responses: can EGFR inhibitors be used as immune response modifiers? Oncoimmunology 2012; 1: 71–74. 54. Marincola FM, Jaffee EM, Hicklin DJ et al. Escape of human solid tumors from Tcell recognition: molecular mechanisms and functional significance. Adv Immunol 2000; 74: 181–273. 55. Leibowitz MS, Andrade Filho PA, Ferrone S et al. Deficiency of activated STAT1 in head and neck cancer cells mediates TAP1-dependent escape from cytotoxic T lymphocytes. Cancer Immunol Immunother 2011; 60: 525–535. 56. You M, Zhao Z. Positive effects of SH2 domain-containing tyrosine phosphatase SHP-1 on epidermal growth factor- and interferon-gamma-stimulated activation of STAT transcription factors in HeLa cells. J Biol Chem 1997; 272: 23376–23381. 57. Grossmann KS, Rosario M, Birchmeier C et al. The tyrosine phosphatase Shp2 in development and cancer. Adv Cancer Res 2010; 106: 53–89. 58. Tao XH, Shen JG, Pan WL et al. Significance of SHP-1 and SHP-2 expression in human papillomavirus infected Condyloma acuminatum and cervical cancer. Pathol Oncol Res 2008; 14: 365–371. 59. Furcht CM, Munoz Rojas AR, Nihalani D et al. Diminished functional role and altered localization of SHP2 in non-small cell lung cancer cells with EGFRactivating mutations. Oncogene 2013; 32: 2346–2355. 60. Schrump DS, Nguyen DM. The epidermal growth factor receptor-STAT pathway in esophageal cancer. Cancer J 2001; 7: 108–111. 61. Kijima T, Niwa H, Steinman RA et al. STAT3 activation abrogates growth factor dependence and contributes to head and neck squamous cell carcinoma tumor growth in vivo. Cell Growth Differ 2002; 13: 355–362. 62. Grandis JR, Drenning SD, Chakraborty A et al. Requirement of Stat3 but not Stat1 activation for epidermal growth factor receptor-mediated cell growth In vitro. J Clin Invest 1998; 102: 1385–1392. 63. Buchanan FG, Wang D, Bargiacchi F et al. Prostaglandin E2 regulates cell migration via the intracellular activation of the epidermal growth factor receptor. J Biol Chem 2003; 278: 35451–35457. 64. Sriuranpong V, Park JI, Amornphimoltham P et al. Epidermal growth factor receptor-independent constitutive activation of STAT3 in head and neck squamous cell carcinoma is mediated by the autocrine/paracrine stimulation of the interleukin 6/gp130 cytokine system. Cancer Res 2003; 63: 2948–2956. 65. Colomiere M, Ward AC, Riley C et al. Cross talk of signals between EGFR and IL6R through JAK2/STAT3 mediate epithelial-mesenchymal transition in ovarian carcinomas. Br J Cancer 2009; 100: 134–144.
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98. Zorn E, Nelson EA, Mohseni M et al. IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood 2006; 108: 1571–1579. 99. Mantovani A, Sica A, Sozzani S et al. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 2004; 25: 677–686. 100. Duluc D, Delneste Y, Tan F et al. Tumor-associated leukemia inhibitory factor and IL-6 skew monocyte differentiation into tumor-associated macrophage-like cells. Blood 2007; 110: 4319–4330. 101. Munn DH, Mellor AL. Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest 2007; 117: 1147–1154. 102. Machiels JP, Subramanian S, Ruzsa A et al. Zalutumumab plus best supportive care versus best supportive care alone in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy: an open-label, randomised phase 3 trial. Lancet Oncol 2011; 12: 333–343. 103. Ramakrishnan MS, Eswaraiah A, Crombet T et al. Nimotuzumab, a promising therapeutic monoclonal for treatment of tumors of epithelial origin. MAbs 2009; 1: 41–48. 104. Allan DG. Nimotuzumab: evidence of clinical benefit without rash. Oncologist 2005; 10: 760–761.
Annals of Oncology 26: 47–57, 2015 doi:10.1093/annonc/mdu225 Published online 5 August 2014
Estimates of benefits and harms of prophylactic use of aspirin in the general population J. Cuzick1*, M. A. Thorat1, C. Bosetti2, P. H. Brown3, J. Burn4, N. R. Cook5, L. G. Ford6, E. J. Jacobs7, J. A. Jankowski8,9, C. La Vecchia2,10, M. Law11, F. Meyskens12, P. M. Rothwell13, H. J. Senn14 & A. Umar15 1 Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK; 2Department of Epidemiology, IRCCS-Istituto di Ricerche Farmacologiche ‘Mario Negri’, Milan, Italy; 3Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, USA; 4 Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK; 5Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston; 6Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda; 7Epidemiology Research Program, American Cancer Society, Atlanta, USA; 8Centre for Biomedical Research–Translational and Stratified Medicine, Peninsula Schools of Medicine and Dentistry, Plymouth University, Plymouth; 9Centre for Digestive Diseases, Blizard Institute of Cell and Molecular Science, Queen Mary University of London, London, UK; 10Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; 11Centre for Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK; 12Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, USA; 13Stroke Prevention Research Unit, Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK; 14Tumor and Breast Center ZeTuP, St Gallen, Switzerland; 15Gastrointestinal and Other Cancers Research Group, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, USA
Received 7 February 2014; revised 14 May 2014; accepted 9 June 2014
Background: Accumulating evidence supports an effect of aspirin in reducing overall cancer incidence and mortality in the general population. We reviewed current data and assessed the benefits and harms of prophylactic use of aspirin in the general population. Methods: The effect of aspirin for site-specific cancer incidence and mortality, cardiovascular events was collated from the most recent systematic reviews. Studies identified through systematic Medline search provided data regarding harmful effects of aspirin and baseline rates of harms like gastrointestinal bleeding and peptic ulcer.
*Correspondence to: Prof. Jack Cuzick, Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Tel: +44-20-7882-3518; Fax: +44-20-7882-3890; E-mail: [email protected]
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected]
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90. Lee SC, Srivastava RM, Lopez-Albaitero A et al. Natural killer (NK): dendritic cell (DC) cross talk induced by therapeutic monoclonal antibody triggers tumor antigen-specific T cell immunity. Immunol Res 2011; 50: 248–254. 91. Rudensky AY. Regulatory T cells and Foxp3. Immunol Rev 2011; 241: 260–268. 92. Sakaguchi S. Regulatory T cells: key controllers of immunologic self-tolerance. Cell 2000; 101: 455–458. 93. Sakaguchi S, Yamaguchi T, Nomura T et al. Regulatory T cells and immune tolerance. Cell 2008; 133: 775–787. 94. Strauss L, Bergmann C, Szczepanski M et al. A unique subset of CD4 +CD25highFoxp3+ T cells secreting interleukin-10 and transforming growth factor-beta1 mediates suppression in the tumor microenvironment. Clin Cancer Res 2007; 13: 4345–4354. 95. Mooradian DL, Purchio AF, Furcht LT. Differential effects of transforming growth factor beta 1 on the growth of poorly and highly metastatic murine melanoma cells. Cancer Res 1990; 50: 273–277. 96. Nishikawa H, Kato T, Tawara I et al. IFN-gamma controls the generation/activation of CD4+ CD25+ regulatory T cells in antitumor immune response. J Immunol 2005; 175: 4433–4440. 97. Larmonier N, Marron M, Zeng Y et al. Tumor-derived CD4(+)CD25(+) regulatory T cell suppression of dendritic cell function involves TGF-beta and IL-10. Cancer Immunol Immunother 2007; 56: 48–59.
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Annals of Oncology Annals of Oncology 26: 40–47, 2015 doi:10.1093/annonc/mdu156 Published online 4 July 2014
Immune biomarkers of anti-EGFR monoclonal antibody therapy S. Trivedi1, F. Concha-Benavente2, R. M. Srivastava1, H. B. Jie1, S. P. Gibson1, N. C. Schmitt1 & R. L. Ferris1,2,3* 1
Department of Otolaryngology, University of Pittsburgh School of Medicine; 2Department of Immunology, University of Pittsburgh; 3Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, USA
Received 22 November 2013; revised 8 April 2014; accepted 9 April 2014
introduction The epidermal growth factor receptor (EGFR) is a member of the ErbB family of four structurally related receptor tyrosine kinases [1]. These transmembrane proteins are composed of an extracellular domain for binding of specific ligands, and an intracellular domain with tyrosine kinase activity. Ligand binding causes dimerization of the receptor which triggers a signaling cascade that promotes cell survival and tissue invasion, while inhibiting apoptosis [2]. EFGR is frequently overexpressed in epithelial malignancies, which corresponds to a decrease in patient survival, providing a target for tumor antigen (TA)-targeted monoclonal antibody (mAb)-based immunotherapy. Cetuximab and panitumumab are two such mAbs which have been incorporated to treatment regimens for colorectal and head and neck cancers [3–11]. As single agents, these antibodies confer clinical responses in 10%–15% of patients with advanced untreated and recurrent metastatic disease [12]. Interestingly, when used in combination with chemotherapy or radiotherapy, the efficacy of these mAbs is often improved with higher response rates, prolonged duration of response and crucially, prolonged patient survival [13, 14].
*Correspondence to: Dr Robert L. Ferris, Cancer Immunology Program, University of Pittsburgh Cancer Institute, 5117 Centre Ave, Suite 2.26b, Pittsburgh, PA 15213, USA. Tel: +1-412-647-4654; E-mail: [email protected]
Although these antibodies gave new hope to those with advanced, therapy-resistant disease, the subpopulation of patients who successfully respond to treatment remains low [15–22]. Cetuximab, the first anti-EGFR mAb to receive regulatory approval, has been extensively studied and, here, we reviewed the immunogenic mechanisms that underlie the antitumor effect of cetuximab and, to some extent, panitumumab, distinguishing these two mAbs clinically and biologically, as well as detailing some of the newer anti-EGFR mAbs currently in the clinical trial stages.
the immunological aspect of anti-EGFR monoclonal antibodies Cetuximab is a murine-human chimeric antibody composed of the variable region of a murine anti-EGFR antibody joined with human IgG1 heavy and light chain regions, which binds to the extracellular domain of the EGF receptor with a twofold greater affinity than its natural ligands EGF and transforming growth factor-α [23–25]. In addition to its role in colorectal carcinoma (CRC), cetuximab is approved by both the FDA and the European Medicines Agency (EMA) for treatment of locally advanced untreated squamous cell carcinoma of the head and neck (SCCHN) in combination with chemoradiotherapy and as a single agent for metastatic or recurrent disease. Binding of cetuximab to the EGFR results in competitive inhibition of
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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The tumor antigen (TA)-targeted monoclonal antibodies (mAb) cetuximab and panitumumab target the human epidermal growth factor receptor and have been integrated into treatment regimens for advanced squamous cell carcinoma of the head and neck (SCCHN). The therapeutic efficacy of these mAbs has been found to be enhanced when combined with radiotherapy and chemotherapy. However, clinical trials indicate that these findings are limited to fewer than 20% of treated patients. Therefore, identifying patients who are likely to benefit from these agents is crucial to improving therapeutic strategies. Interestingly, it has been noted that TA-targeted mAbs mediate their effects by contributing to cell-mediated cytotoxicity in addition to inhibition of downstream signaling pathways. Here, we describe the potential immunogenic mechanisms underlying these clinical findings, their role in the varied clinical response and identify the putative biomarkers of antitumor activity. We review potential immunological biomarkers that affect mAb therapy in SCCHN patients, the implications of these findings and how they translate to the clinical scenario, which are critical to improving patient selection and ultimately outcomes for patients undergoing therapy. Key words: EGFR, immune biomarkers, monoclonal antibodies, head and neck cancer
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has a significant role to play in their effectiveness [34]. Cetuximab treatment of SCCHN cells in vitro does not result in apoptosis or lysis of tumor cells; [20] this only occurs in the presence of lymphocytes, supporting an immune-mediated mechanism contributing to the antitumor effect of anti-EGFR mAb therapy. ADCC is a lytic reaction characterized by cetuximab and panitumumab coating EGFR on the surface of tumor cells and binding to FcγRs expressed on immune effector cells, activating them and resulting in lysis of the antibody-coated target cells (Figure 1). Cetuximab-mediated ADCC reactions can be enhanced by cytokines, including interleukin 12 (IL-12), interleukin 2 and other NK cell-activating cytokines thus indicating the importance of NK cell function in effective ADCC reactions. Studies in both breast cancer and SCCHN indicate that cytokine activation of NK cells results in enhanced NK cell lytic activity against cetuximab-coated cells as well as increased antitumor effects mediated by these activated NK cells [35, 36]. Three classes of FcγR encoded by eight genes have been identified in humans, FcγRI (CD64), FcγRII (CD32), and FcγRIII (CD16a). Some FcγR display allelic polymorphisms which generate allotypes that have been reported to be functionally relevant in the ADCC mechanism [21]. A clinically relevant example of this is seen in the gene encoding FcγRIIIa, where a single-nucleotide substitution at position 158 results in the substitution of phenylalanine (F) by valine (V) in the IgG-binding domain, which results in varying patient response to cetuximab treatment [16]. Unlike in CRC where better clinical response to cetuximab therapy has been shown to correlate with the FcγRIIIa VV or FF genotypes [16, 22, 37], in vitro studies in SCCHN appear to indicate a correlation with the FcγRIIIa VV genotype and more potent ADCC [21, 38]. Clinical data are not yet available from cetuximab clinical trials but a retrospective cohort showed a nonsignificant association with the V-encoding allele. Interestingly, this phenomenon is also reported in patients treated with the
Fc-gamma receptor polymorphisms and clinical response Although anti-EGFR mAbs inhibit EGFR tyrosine phosphorylation and subsequent downstream signaling, evidence suggests that triggering of ADCC mediated by mAb-activated NK cells
TGFβ
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Cytolysis EGFR
Tumor cell Figure 1. Antibody-dependent, cell-mediated cytotoxicity (ADCC). ADCC mediated by tumor antigen (TA)-targeted monoclonal antibodies (mAbs) in the tumor microenvironment. TA-positive tumor cells are exposed to TA-targeted mAbs which leads to opsonization through binding of cetuximab and panitumumab to the TA epitopes expressed on tumor targets. NK cell recognition of opsonized tumor cells is mediated via Fcgamma receptor (FcγR) III/CD16 while FcγRIIa/CD32 mediates recognition. This effect is diminished by regulatory T cells (Treg) which exert a suppressive function on effector immune cells through secretion of interleukin 10, transforming growth factor-β and adenosine into the tumor microenvironment.
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ligand binding and receptor phosphorylation as well as associated downstream signaling while concomitantly inducing receptor downregulation through dimerization and internalization [26]. The three main pathways downstream of EGFR are the MAPK, PI3K/AKT and JAK/signal transducer and activator of transcription (STAT) pathways [27–29]. However, in addition to inhibition of these mitogenic pathways, the effects of cetuximab therapy may also be mediated by antibody-dependent, cellmediated cytotoxicity (ADCC) [30], complement-mediated cytotoxicity [15] and adaptive immunity-mediated by CD8+ cytotoxic T lymphocytes (CTL) [31]. Panitumumab is a fully human IgG2 mAb which also targets the extracellular domain of EGFR. It binds the EGFR with great affinity (Kd = 1.33 ± 0.29 nmol/l) and was developed with the intention of causing fewer hypersensitivity reactions than cetuximab [32]. However, as an IgG2 isotype, it has lower immunogenicity potential, through poor Fc-gamma receptor (FcγR) binding [16]. Approved by both the FDA and EMA for use in CRC, panitumumab has not yet been approved for use in SCCHN although several clinical trials are reported or currently underway [33]. In addition to receptor downregulation and inhibition of downstream signaling of the EGFR, the clinical efficacy of panitumumab is believed to be mediated by induction of cell cycle arrest and inhibition of angiogenesis [17, 18], as well as facilitating ADCC, potentially through FcγRIIa on neutrophils [19] although to a lesser degree than cetuximab therapy.
reviews HER2-specific mAb trastuzumab for breast cancer [39, 40]. Our in vivo studies seem to indicate that FcγRIIIa genotype is not associated with disease-specific survival in a retrospective cohort of 107 cetuximab-treated patients with SCCHN [31]. As yet, no prospectively collected clinical data in SCCHN have been published confirming genotype as a useful biomarker of clinical activity.
modulation of the human leukocyte antigen class I and antigen-processing machinery expression by EGFR-specific mAb
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signal transducer and activator of transcription 3 as a mechanism for SCCHN immune escape EGFR overexpression in SCCHN cells induces the constitutive activation of STAT3, a known oncogenic transcription factor which results in tumor growth [60–63], and immunosuppression [52, 55]. Other receptors from the ErbB/HER family can also be ligated by their tumor-overexpressed ligands causing EGFR-independent STAT3 activation in an autocrine or paracrine fashion. Notably, the interleukin 6 (IL-6) receptor (IL-6R)/CD130 signaling complex has also been shown to be a major pathway involved in EGFR-independent STAT3 activation and tumorigenesis [64–66]; indeed, it is overexpressed in SCCHN cells and its detection is correlated with poor survival in SCCHN patients [67]. Thus, the expected cetuximabmediated growth inhibition of SCCHN via blocking EGFRdependent survival signals may not be fully effective, since STAT3 constitutive activation takes place through alternative pathways, such as IL-6/gp130. SCCHN cells exhibit a constitutively active STAT3 that blocks apoptosis and induces proliferation, angiogenesis and immune evasion [68, 69]. STAT3 is considered an oncogene and its inhibition leads to apoptosis in vitro and to an impaired tumor growth in xenografted mouse models [70, 71]. STAT3 plays a major role in promoting tumor immune evasion. Previous work shows that it not only inhibits production of inflammatory signals from tumor cells, but also production of immunosuppressive mediators, thus inducing a tolerant tumor microenvironment [72, 73]. Due to this situation, SCCHN cells may evade cetuximab-dependent immune effector cell tumor cytolysis, as well as EGFR signaling inhibition, through mechanisms discussed below and shown in Figure 2. EGFR-mediated STAT3 activation induces the expression of vascular endothelial growth factor (VEGF), IL-6 and interleukin 10 (IL-10) in many tumors including melanoma [64, 67]. Increased levels of VEGF have been found to induce tumor growth, metastasis and resistance to treatment in SCCHN [74, 75]. In a recent phase II clinical trial, the addition of bevacizumab (a humanized anti-VEGF-A IgG1 mAb) with cetuximab therapy was shown to induce a 16% clinical response rate in 46 patients with recurrent or metastatic SCCHN [76], suggesting a potential role for combination therapy, though further studies are needed to validate these findings. IL-6, IL-10 and VEGF are known to activate STAT3 in tumor-associated immune cells, providing a feed-forward mechanism to ensure a STAT3-dominated tumor permissive microenvironment. Tumor-secreted transforming growth factor-β (TGF-β), VEGF and IL-10 induce T-cell tolerance through inhibition of dendritic cell (DC) differentiation and maturation [77, 78]. Moreover, blocking STAT3 in macrophages-induced restoration of T-cell responsiveness by restoring the secretion of IL12 and CCL5. Likewise, IL-10 protects tumor cells from CTL lysis by downregulation of APM components (TAP1, TAP2) and surface HLA class I expression [79, 80]. Thus, immunosuppressive cytokines induced by EGFR-JAK2-STAT3 activation, potentially inhibited by EGFR-targeted mAb, may serve as biomarkers of response to anti-EGFR therapy.
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Anti-EGFR mAb therapy is associated with proinflammatory side-effects, the most common of which is the development of a characteristic skin rash [41, 42] suggesting that EGFR signaling is involved in the control of immunoregulatory genes. Interestingly, the skin rash may correlate with improved response to therapy and better clinical outcome for cetuximab-treated patients [43]. Overexpression of EGFR associated with SCCHN has been shown to repress expression of the human leukocyte antigen (HLA) class I and antigen-processing machinery (APM) components [44–47], a phenomenon associated with tumor cell escapes from CTL recognition and lysis [48]. The process of tagging endogenous proteins for degradation and processing before formation of the HLA class I–peptide complexes to be presented on the cell surface involves the cooperation of multiple components within the APM of antigen-presenting cells. These HLA class I– peptide complexes are then recognized by T cells expressing the corresponding T-cell receptors. The resulting impaired tumor antigen (TA) processing and presentation leads to poor recognition of tumor cells by CTL and the development of an immune escape phenotype that correlates with poor clinical outcome [48– 51]. Although the exact molecular mechanisms for this remain under investigation [52], these effects appear to be ameliorated by anti-EGFR antibody therapy [53]. Cetuximab has been shown to upregulate HLA class I antigens on the level of gene transcription and correlates with increased cutaneous expression of HLA class I and II proteins in patients who developed skin rash upon cetuximab therapy [44]. The cytokines and molecular signals that regulate the finely tuned APM are often disrupted in SCCHN [49, 54]. One such molecular signal is the transcription factor STAT1. The activated form of STAT1, phospho-STAT1 (pSTAT1) and has been shown to be necessary for APM expression and subsequent T-cell recognition [55, 56]. The characteristic low basal pSTAT1 level which is seen in SCCHN has been attributed to Src homology-2 domain-containing phosphatase (SHP2), a known negative regulator of the JAK-STAT1 signal transduction pathway, which is frequently overexpressed in multiple malignancies [52, 57, 58]. While overexpression of EGFR has not been shown to be correlated with SHP2 increase in SCCHN, in other malignancies, such as lung cancer, activating mutations of EGFR have been linked to activation of SHP2 [59]. Studies are currently underway in SCCHN to investigate the role that EGFR signaling downregulation by anti-EGFR mAb may have in inhibiting SHP2 and subsequent increase in pSTAT1, which has been shown to restore antitumor immunity in the tumor microenvironment.
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Figure 2. Signal transducer and activator of transcription 3 (STAT3) pathways involved in immune escape. epidermal growth factor receptor (EGFR) overexpression noted in squamous cell carcinoma of the head and neck results in constitutive STAT3 activation through the JAK/STAT pathway. STAT3 is a known oncogenic transcription factor which results in tumor growth and immune suppression, in part due to the induction of immunosuppressive cytokines such as interleukin 6 (IL-6), vascular endothelial growth factor (VEGF) and interleukin 10 (IL-10). The IL-6R/CD130 signaling complex, also upregulated in squamous cell carcinoma of the head and neck, is a major pathway in EGFR-independent STAT3 activation and may contribute to the modest response seen in therapy with EGFR-blocking antibodies. Interferon-γ (IFN-γ) activates STAT1 phosphorylation which opposes the action of STAT3, EGFR overexpression activates SHP2 which conversely inhibits the phosphorylation of STAT1.
HPV status In the USA and Northern Europe, the incidence rate of some oropharyngeal cancers, particularly those of the tonsil and tongue base have steadily increased since the 1970s. This is especially noted in younger patients without the usual recognized risk factors for SCCHN [81–83]. Along with other etiological factors, the primary cause for this has been attributed to persistent infection with high-risk human papillomavirus (HPV) [84, 85]. Tumors that are positive for HPV have a different biology and phenotypical features than HPV-negative tumors. They tend to be poorly differentiated with scant keratinization [86]. The difference in HPV-positive and -negative cancers is noted in prognostic outcomes for the patient, with HPV-positive disease being exquisitely radiosensitive and therefore having more favorable clinical outcomes than patients with smoking-related SCCHN [87, 88]. Results of a multicenter, randomized phase III trial by the Radiation Therapy Oncology Group (RTOG) looking at concurrent radiation and cisplatin versus concurrent radiation, cisplatin and cetuximab for stage III and IV SCCHN suggested that patients with HPV-positive tumors may not benefit from
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addition of cetuximab therapy to cisplatin. An ongoing RTOG trial 1016 aims to evaluate the impact of EGFR-specific mAb, cetuximab versus cisplatin in the context of HPV + disease. A similar phase III SPECTRUM trial that looked at the safety and efficacy of panitumumab in recurrent or metastatic SCCHN found that Panitumumab plus cisplatin improved both overall survival (OS) and progression-free survival (PFS) in HPV-positive tumors, and showed no incremental benefit in patients with HPV-negative tumors. HPV status was classified differently in the RTOG and SPECTRUM trials, clouding the interpretation of these results. Further studies are warranted to delineate the role of HPV status as a potential immune biomarker of anti-EGFR monoclonal antibody therapy.
regulatory T cells and tumor-associated macrophages EGFR-specific CTL have been identified in SCCHN patients but not in healthy donors suggesting that EGFR may function as an immunogenic TA in cancer patients [89]. During therapy with
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Increased antigen presentation
SHP2
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newer EGFR-specific mAb Several novel anti-EGFR antibodies have recently been brought to the market, although none are currently approved for use against SCCHN within the USA, there are currently ongoing clinical trials underway to investigate their efficacy. Zalutumumab is a fully human IgG1 mAb, which was tested as a second-line agent in a recent phase III randomized clinical trial of 286 patients with recurrent or metastatic disease refractory to platinum-based therapy. SCCHN patients who received zalutumumab with supportive care versus supportive care alone demonstrated no statistically significant improvement in OS between either group. Of note however, the PFS appeared longer
| Trivedi et al.
in the zalutumumab-treated group compared with supportive therapy alone [102]. Nimotuzumab is a humanized IgG1 mAb currently approved for use in the management of SCCHN in countries outside the USA and Europe. A potential advantage of nimotuzumab is its lower immunogenic side-effects profile [103]. Initial phase I studies revealed an absence or mild skin toxicity and hypersensitivity reactions [104].
summary Immune therapy continues to be an evolving area of cancer therapy, in order to better evaluate patient response to therapy, certain immune biomarkers should be identified and monitored; here, we have described the potential immune biomarkers of cetuximab and panitumumab therapy. Although the importance of FcγR polymorphisms in the ADCC reaction has been noted in the breast cancer and CRC models, it is yet to be seen whether it is a useful biomarker in the setting of SCCHN. In vitro studies indicate a correlation with the FcγRIIIa VV genotype and more potent ADCC reactions; however, this finding did not appear to correlate with disease-specific survival in a large retrospective study involving cetuximab and SCCHN. Future prospective cohorts must be interrogated. Constitutive STAT3 activation seen in SCCHN promotes tumor immune evasion, and contributes to induction of a tolerant tumor microenvironment. Additionally, it mediates expression of cytokines and growth factors known to promote tumorigenesis and correlates with poor clinical outcomes, an effect that may take place through alternative, EGFR-independent pathways. Clinical trials looking at combining EGFR blockade as well as blockade of pathways downstream of STAT3 may indicate a role for STAT3 or TGF-β modulation in successful immunotherapy. The identification of EGFR-specific CTL in SCCHN patients, which increase in frequency during treatment with TA-targeted mAbs suggests that EGFR may function as an immunogenic protein in these patients, and that cetuximab may drive NK: DC priming of cellular immunity. However, the strong suppressive function of Treg populations in the circulation of these patients may be responsible for the lack of antitumor effects seen with despite this elevated frequency of EGFR-specific CTL in SCCHN patients. The suppressive functions of Tregs are mediated primarily through TGF-β and IL-10 which can be additionally be secreted by Tregs in a STAT3-dependent fashion, further propagating the immunosuppressive signals. As the field of TA-targeted mAb-based immunotherapy continues to expand, a greater understanding of the immunogenic mechanisms that underlie their antitumor effect is necessary. Future mAb trials should monitor immune biomarkers and correlate these with patient response.
funding This review was supported in part by National Institutes of Health grants P30CA047904, P50CA097190 and R01DE19727.
disclosure RLF has received research funding from Bristol-Myers Squibb and Amgen. He has served as a consultant to Bristol-Myers
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anti-EGFR mAbs there is an observed enhancement of EGFRspecific CTL frequencies, the generation of these CTL appears to be initiated by cetuximab-induced NK cell activation [31, 90]. Despite the elevated frequency of EGFR-specific CTL in SCCHN patients, it was noted that these CTL did not sufficiently inhibit tumor growth. One explanation for finding has been proposed to be due to is elevated levels of suppressive regulatory T-cell (Treg) populations in the circulation and tumor sites of these patients. Tregs possess a strong suppressive function, through TGF-β, IL10 and adenosine produced by the ecto-enzymes CD39 and CD73, and are believed to result from chronically activated T cells [91]. CD25+CD4+ Treg cells constitutively express the transcription factor Foxp3 and regulate immune self-tolerance by suppressing aberrant or excessive immune responses which may be harmful to the host. Abnormalities in Treg function are seen in many autoimmune and inflammatory diseases [92, 93]. Within the tumor microenvironment, it is believed that the development of Tregs results from chronic exposure of T cells to selfantigens, including EGFR. Therefore, although CD8+ T cells are present in some SCCHN patients, their antitumor activity may be suppressed by Tregs [94] (Jie HB, in press). Anti-EGFR mAb therapy significantly increases both the frequency of EGFR-specific TIL and Tregs in both the circulation and tumor sites of patients with SCCHN. Several additional cytokine interactions are involved in generation of Tregs in SCCHN patients. TGF-β, a known immunosuppressive cytokine, is found to be present at high concentrations in plasma of cancer patients and is associated with disease progression and poor response to immunotherapy. TGF-β production is characteristic of many malignancies including melanoma, breast and colon cancer and is known to prevent proper CTL generation and function [95]; however, TGF-β secretion by SCCHN is still not well characterized. Interestingly, TGFβ is involved in the generation of Tregs that are known to inhibit CD8+ T-cell activation, interferon-γ production and proliferation [96]. Additionally, Tregs can secret TGF-β and IL-10 in a STAT3-dependent fashion further propagating the immunosuppressive signals [97, 98]. This intricate tumor cellular network also includes TAMs, which are induced by monocyte exposure to tumor-secreted IL-6, IL-10 and VEGF [99]. TAMs suppress DC maturation in an IL-10-dependent manner that in turn inhibits CD8+ T-cell proliferation and function [100, 101]. TAM-derived IL-10 can also induce differentiation of naive T cells into Tregs [98], and thus may suppress mAb-induced cellular immunity in the tumor microenvironment.
Annals of Oncology
Annals of Oncology
Squibb, and VentiRx. All remaining authors have declared no conflicts of interest.
references
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23. Gill GN, Kawamoto T, Cochet C et al. Monoclonal anti-epidermal growth factor receptor antibodies which are inhibitors of epidermal growth factor binding and antagonists of epidermal growth factor binding and antagonists of epidermal growth factor-stimulated tyrosine protein kinase activity. J Biol Chem 1984; 259: 7755–7760. 24. Goldstein NI, Prewett M, Zuklys K et al. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res 1995; 1: 1311–1318. 25. Kim ES, Khuri FR, Herbst RS. Epidermal growth factor receptor biology (IMCC225). Curr Opin Oncol 2001; 13: 506–513. 26. Sharafinski ME, Ferris RL, Ferrone S et al. Epidermal growth factor receptor targeted therapy of squamous cell carcinoma of the head and neck. Head Neck 2010; 32: 1412–1421. 27. Kruger JS, Reddy KB. Distinct mechanisms mediate the initial and sustained phases of cell migration in epidermal growth factor receptor-overexpressing cells. Mol Cancer Res 2003; 1: 801–809. 28. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002; 2: 489–501. 29. Ellerbroek SM, Halbleib JM, Benavidez M et al. Phosphatidylinositol 3-kinase activity in epidermal growth factor-stimulated matrix metalloproteinase-9 production and cell surface association. Cancer Res 2001; 61: 1855–1861. 30. Bleeker WK, Lammerts van Bueren JJ, van Ojik HH et al. Dual mode of action of a human anti-epidermal growth factor receptor monoclonal antibody for cancer therapy. J Immunol 2004; 173: 4699–4707. 31. Srivastava RM, Lee SC, Andrade Filho PA et al. Cetuximab-activated natural killer and dendritic cells collaborate to trigger tumor antigen-specific T-cell immunity in head and neck cancer patients. Clin Cancer Res 2013; 19: 1858–1872. 32. Yang XD, Jia XC, Corvalan JR et al. Development of ABX-EGF, a fully human antiEGF receptor monoclonal antibody, for cancer therapy. Crit Rev Oncol Hematol 2001; 38: 17–23. 33. Vermorken JB, Stohlmacher-Williams J, Davidenko I et al. Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial. Lancet Oncol 2013; 14: 697–710. 34. Ferris RL, Jaffee EM, Ferrone S. Tumor antigen-targeted, monoclonal antibodybased immunotherapy: clinical response, cellular immunity, and immunoescape. J Clin Oncol 2010; 28: 4390–4399. 35. Luedke E, Jaime-Ramirez AC, Bhave N et al. Cetuximab therapy in head and neck cancer: immune modulation with interleukin-12 and other natural killer cellactivating cytokines. Surgery 2012; 152: 431–440. 36. Roda JM, Joshi T, Butchar JP et al. The activation of natural killer cell effector functions by cetuximab-coated, epidermal growth factor receptor positive tumor cells is enhanced by cytokines. Clin Cancer Res 2007; 13: 6419–6428. 37. Pander J, Gelderblom H, Antonini NF et al. Correlation of FCGR3A and EGFR germline polymorphisms with the efficacy of cetuximab in KRAS wild-type metastatic colorectal cancer. Eur J Cancer 2010; 46: 1829–1834. 38. Taylor RJ, Chan SL, Wood A et al. FcgammaRIIIa polymorphisms and cetuximab induced cytotoxicity in squamous cell carcinoma of the head and neck. Cancer Immunol Immunother 2009; 58: 997–1006. 39. Musolino A, Naldi N, Bortesi B et al. Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J Clin Oncol 2008; 26: 1789–1796. 40. Tamura K, Shimizu C, Hojo T et al. FcgammaR2A and 3A polymorphisms predict clinical outcome of trastuzumab in both neoadjuvant and metastatic settings in patients with HER2-positive breast cancer. Ann Oncol 2011; 22: 1302–1307. 41. Li T, Perez-Soler R. Skin toxicities associated with epidermal growth factor receptor inhibitors. Target Oncol 2009; 4: 107–119. 42. Abdullah SE, Haigentz M, Jr, Piperdi B. Dermatologic toxicities from monoclonal antibodies and tyrosine kinase inhibitors against EGFR: pathophysiology and management. Chemother Res Pract 2012; 2012: 351210. 43. Perez-Soler R, Saltz L. Cutaneous adverse effects with HER1/EGFR-targeted agents: is there a silver lining? J Clin Oncol 2005; 23: 5235–5246. 44. Pollack BP, Sapkota B, Cartee TV. Epidermal growth factor receptor inhibition augments the expression of MHC class I and II genes. Clin Cancer Res 2011; 17: 4400–4413.
doi:10.1093/annonc/mdu156 |
Downloaded from http://annonc.oxfordjournals.org/ at Sussex Language Institute on July 28, 2015
1. Bublil EM, Yarden Y. The EGF receptor family: spearheading a merger of signaling and therapeutics. Curr Opin Cell Biol 2007; 19: 124–134. 2. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001; 2: 127–137. 3. Langer CJ. Targeted therapy in head and neck cancer: state of the art 2007 and review of clinical applications. Cancer 2008; 112: 2635–2645. 4. Blick SK, Scott LJ. Cetuximab: a review of its use in squamous cell carcinoma of the head and neck and metastatic colorectal cancer. Drugs 2007; 67: 2585–2607. 5. Frampton JE. Cetuximab: a review of its use in squamous cell carcinoma of the head and neck. Drugs 2010; 70: 1987–2010. 6. Bourhis J, Lefebvre JL, Vermorken JB. Cetuximab in the management of locoregionally advanced head and neck cancer: expanding the treatment options? Eur J Cancer 2010; 46: 1979–1989. 7. Cripps C, Winquist E, Devries MC et al. Epidermal growth factor receptor targeted therapy in stages III and IV head and neck cancer. Curr Oncol 2010; 17: 37–48. 8. Holubec L, Liska V, Matejka VM et al. The role of cetuximab in the treatment of metastatic colorectal cancer. Anticancer Res 2012; 32: 4007–4011. 9. Spiro H. Cetuximab for metastatic colorectal cancer. N Engl J Med 2009; 361: 95; author reply 96–97. 10. Amado RG, Wolf M, Peeters M et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008; 26: 1626–1634. 11. Noguchi T, Ritter G, Nishikawa H. Antibody-based therapy in colorectal cancer. Immunotherapy 2013; 5: 533–545. 12. Adams GP, Weiner LM. Monoclonal antibody therapy of cancer. Nat Biotechnol 2005; 23: 1147–1157. 13. Bonner JA, Harari PM, Giralt J et al. Radiotherapy plus cetuximab for squamouscell carcinoma of the head and neck. N Engl J Med 2006; 354: 567–578. 14. Cunningham D, Humblet Y, Siena S et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004; 351: 337–345. 15. Dechant M, Weisner W, Berger S et al. Complement-dependent tumor cell lysis triggered by combinations of epidermal growth factor receptor antibodies. Cancer Res 2008; 68: 4998–5003. 16. Bibeau F, Lopez-Crapez E, Di Fiore F et al. Impact of Fc{gamma}RIIa-Fc{gamma} RIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with cetuximab plus irinotecan. J Clin Oncol 2009; 27: 1122–1129. 17. Foon KA, Yang XD, Weiner LM et al. Preclinical and clinical evaluations of ABXEGF, a fully human anti-epidermal growth factor receptor antibody. Int J Radiat Oncol Biol Phys 2004; 58: 984–990. 18. Lynch DH, Yang XD. Therapeutic potential of ABX-EGF: a fully human antiepidermal growth factor receptor monoclonal antibody for cancer treatment. Semin Oncol 2002; 29: 47–50. 19. Schneider-Merck T, Lammerts van Bueren JJ, Berger S et al. Human IgG2 antibodies against epidermal growth factor receptor effectively trigger antibodydependent cellular cytotoxicity but, in contrast to IgG1, only by cells of myeloid lineage. J Immunol 2010; 184: 512–520. 20. Lopez-Albaitero A, Ferris RL. Immune activation by epidermal growth factor receptor specific monoclonal antibody therapy for head and neck cancer. Arch Otolaryngol Head Neck Surg 2007; 133: 1277–1281. 21. Lopez-Albaitero A, Lee SC, Morgan S et al. Role of polymorphic Fc gamma receptor IIIa and EGFR expression level in cetuximab mediated, NK cell dependent in vitro cytotoxicity of head and neck squamous cell carcinoma cells. Cancer Immunol Immunother 2009; 58: 1853–1864. 22. Zhang W, Gordon M, Schultheis AM et al. FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab. J Clin Oncol 2007; 25: 3712–3718.
reviews
reviews
| Trivedi et al.
66. Gao SP, Mark KG, Leslie K et al. Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J Clin Invest 2007; 117: 3846–3856. 67. Duffy SA, Taylor JM, Terrell JE et al. Interleukin-6 predicts recurrence and survival among head and neck cancer patients. Cancer 2008; 113: 750–757. 68. Leeman RJ, Lui VW, Grandis JR. STAT3 as a therapeutic target in head and neck cancer. Expert Opin Biol Ther 2006; 6: 231–241. 69. Regis G, Pensa S, Boselli D et al. Ups and downs: the STAT1:STAT3 seesaw of Interferon and gp130 receptor signalling. Semin Cell Dev Biol 2008; 19: 351–359. 70. Fletcher S, Drewry JA, Shahani VM et al. Molecular disruption of oncogenic signal transducer and activator of transcription 3 (STAT3) protein. Biochem Cell Biol 2009; 87: 825–833. 71. Zhang X, Zhang J, Wang L et al. Therapeutic effects of STAT3 decoy oligodeoxynucleotide on human lung cancer in xenograft mice. BMC Cancer 2007; 7: 149. 72. Wang T, Niu G, Kortylewski M et al. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med 2004; 10: 48–54. 73. Kortylewski M, Kujawski M, Wang T et al. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med 2005; 11: 1314–1321. 74. Smith BD, Smith GL, Carter D et al. Prognostic significance of vascular endothelial growth factor protein levels in oral and oropharyngeal squamous cell carcinoma. J Clin Oncol 2000; 18: 2046–2052. 75. Riedel F, Gotte K, Schwalb J et al. Serum levels of vascular endothelial growth factor in patients with head and neck cancer. Eur Arch Otorhinolaryngol 2000; 257: 332–336. 76. Argiris A, Kotsakis AP, Hoang T et al. Cetuximab and bevacizumab: preclinical data and phase II trial in recurrent or metastatic squamous cell carcinoma of the head and neck. Ann Oncol 2013; 24: 220–225. 77. Gabrilovich DI, Chen HL, Girgis KR et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 1996; 2: 1096–1103. 78. Yang AS, Lattime EC. Tumor-induced interleukin 10 suppresses the ability of splenic dendritic cells to stimulate CD4 and CD8 T-cell responses. Cancer Res 2003; 63: 2150–2157. 79. Yue FY, Dummer R, Geertsen R et al. Interleukin-10 is a growth factor for human melanoma cells and down-regulates HLA class-I, HLA class-II and ICAM-1 molecules. Int J Cancer 1997; 71: 630–637. 80. Salazar-Onfray F, Charo J, Petersson M et al. Down-regulation of the expression and function of the transporter associated with antigen processing in murine tumor cell lines expressing IL-10. J Immunol 1997; 159: 3195–3202. 81. Shiboski CH, Schmidt BL, Jordan RC. Tongue and tonsil carcinoma: increasing trends in the U.S. population ages 20–44 years. Cancer 2005; 103: 1843–1849. 82. Conway DI, Stockton DL, Warnakulasuriya KA et al. Incidence of oral and oropharyngeal cancer in United Kingdom (1990–1999)—recent trends and regional variation. Oral Oncol 2006; 42: 586–592. 83. Hammarstedt L, Dahlstrand H, Lindquist D et al. The incidence of tonsillar cancer in Sweden is increasing. Acta Otolaryngol 2007; 127: 988–992. 84. Ramqvist T, Dalianis T. An epidemic of oropharyngeal squamous cell carcinoma (OSCC) due to human papillomavirus (HPV) infection and aspects of treatment and prevention. Anticancer Res 2011; 31: 1515–1519. 85. Marur S, D’Souza G, Westra WH et al. HPV-associated head and neck cancer: a virus-related cancer epidemic. Lancet Oncol 2010; 11: 781–789. 86. Wilczynski SP, Lin BT, Xie Y et al. Detection of human papillomavirus DNA and oncoprotein overexpression are associated with distinct morphological patterns of tonsillar squamous cell carcinoma. Am J Pathol 1998; 152: 145–156. 87. Furniss CS, McClean MD, Smith JF et al. Human papillomavirus 16 and head and neck squamous cell carcinoma. Int J Cancer 2007; 120: 2386–2392. 88. Fakhry C, Gillison ML. Clinical implications of human papillomavirus in head and neck cancers. J Clin Oncol 2006; 24: 2606–2611. 89. Hoffmann TK, Schirlau K, Sonkoly E et al. A novel mechanism for anti-EGFR antibody action involves chemokine-mediated leukocyte infiltration. Int J Cancer 2009; 124: 2589–2596.
Volume 26 | No. 1 | January 2015
Downloaded from http://annonc.oxfordjournals.org/ at Sussex Language Institute on July 28, 2015
45. Bandoh N, Ogino T, Katayama A et al. HLA class I antigen and transporter associated with antigen processing downregulation in metastatic lesions of head and neck squamous cell carcinoma as a marker of poor prognosis. Oncol Rep 2010; 23: 933–939. 46. Ogino T, Bandoh N, Hayashi T et al. Association of tapasin and HLA class I antigen down-regulation in primary maxillary sinus squamous cell carcinoma lesions with reduced survival of patients. Clin Cancer Res 2003; 9: 4043–4051. 47. Ogino T, Shigyo H, Ishii H et al. HLA class I antigen down-regulation in primary laryngeal squamous cell carcinoma lesions as a poor prognostic marker. Cancer Res 2006; 66: 9281–9289. 48. Lopez-Albaitero A, Nayak JV, Ogino T et al. Role of antigen-processing machinery in the in vitro resistance of squamous cell carcinoma of the head and neck cells to recognition by CTL. J Immunol 2006; 176: 3402–3409. 49. Meissner M, Reichert TE, Kunkel M et al. Defects in the human leukocyte antigen class I antigen processing machinery in head and neck squamous cell carcinoma: association with clinical outcome. Clin Cancer Res 2005; 11: 2552–2560. 50. Ferris RL, Hunt JL, Ferrone S. Human leukocyte antigen (HLA) class I defects in head and neck cancer: molecular mechanisms and clinical significance. Immunol Res 2005; 33: 113–133. 51. Ferris RL, Whiteside TL, Ferrone S. Immune escape associated with functional defects in antigen-processing machinery in head and neck cancer. Clin Cancer Res 2006; 12: 3890–3895. 52. Leibowitz MS, Srivastava RM, Andrade Filho PA et al. SHP2 is overexpressed and inhibits pSTAT1-mediated APM component expression, T-cell attracting chemokine secretion, and CTL recognition in head and neck cancer cells. Clin Cancer Res 2013; 19: 798–808. 53. Pollack BP. EGFR inhibitors, MHC expression and immune responses: can EGFR inhibitors be used as immune response modifiers? Oncoimmunology 2012; 1: 71–74. 54. Marincola FM, Jaffee EM, Hicklin DJ et al. Escape of human solid tumors from Tcell recognition: molecular mechanisms and functional significance. Adv Immunol 2000; 74: 181–273. 55. Leibowitz MS, Andrade Filho PA, Ferrone S et al. Deficiency of activated STAT1 in head and neck cancer cells mediates TAP1-dependent escape from cytotoxic T lymphocytes. Cancer Immunol Immunother 2011; 60: 525–535. 56. You M, Zhao Z. Positive effects of SH2 domain-containing tyrosine phosphatase SHP-1 on epidermal growth factor- and interferon-gamma-stimulated activation of STAT transcription factors in HeLa cells. J Biol Chem 1997; 272: 23376–23381. 57. Grossmann KS, Rosario M, Birchmeier C et al. The tyrosine phosphatase Shp2 in development and cancer. Adv Cancer Res 2010; 106: 53–89. 58. Tao XH, Shen JG, Pan WL et al. Significance of SHP-1 and SHP-2 expression in human papillomavirus infected Condyloma acuminatum and cervical cancer. Pathol Oncol Res 2008; 14: 365–371. 59. Furcht CM, Munoz Rojas AR, Nihalani D et al. Diminished functional role and altered localization of SHP2 in non-small cell lung cancer cells with EGFRactivating mutations. Oncogene 2013; 32: 2346–2355. 60. Schrump DS, Nguyen DM. The epidermal growth factor receptor-STAT pathway in esophageal cancer. Cancer J 2001; 7: 108–111. 61. Kijima T, Niwa H, Steinman RA et al. STAT3 activation abrogates growth factor dependence and contributes to head and neck squamous cell carcinoma tumor growth in vivo. Cell Growth Differ 2002; 13: 355–362. 62. Grandis JR, Drenning SD, Chakraborty A et al. Requirement of Stat3 but not Stat1 activation for epidermal growth factor receptor-mediated cell growth In vitro. J Clin Invest 1998; 102: 1385–1392. 63. Buchanan FG, Wang D, Bargiacchi F et al. Prostaglandin E2 regulates cell migration via the intracellular activation of the epidermal growth factor receptor. J Biol Chem 2003; 278: 35451–35457. 64. Sriuranpong V, Park JI, Amornphimoltham P et al. Epidermal growth factor receptor-independent constitutive activation of STAT3 in head and neck squamous cell carcinoma is mediated by the autocrine/paracrine stimulation of the interleukin 6/gp130 cytokine system. Cancer Res 2003; 63: 2948–2956. 65. Colomiere M, Ward AC, Riley C et al. Cross talk of signals between EGFR and IL6R through JAK2/STAT3 mediate epithelial-mesenchymal transition in ovarian carcinomas. Br J Cancer 2009; 100: 134–144.
Annals of Oncology
Annals of Oncology
98. Zorn E, Nelson EA, Mohseni M et al. IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood 2006; 108: 1571–1579. 99. Mantovani A, Sica A, Sozzani S et al. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 2004; 25: 677–686. 100. Duluc D, Delneste Y, Tan F et al. Tumor-associated leukemia inhibitory factor and IL-6 skew monocyte differentiation into tumor-associated macrophage-like cells. Blood 2007; 110: 4319–4330. 101. Munn DH, Mellor AL. Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest 2007; 117: 1147–1154. 102. Machiels JP, Subramanian S, Ruzsa A et al. Zalutumumab plus best supportive care versus best supportive care alone in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy: an open-label, randomised phase 3 trial. Lancet Oncol 2011; 12: 333–343. 103. Ramakrishnan MS, Eswaraiah A, Crombet T et al. Nimotuzumab, a promising therapeutic monoclonal for treatment of tumors of epithelial origin. MAbs 2009; 1: 41–48. 104. Allan DG. Nimotuzumab: evidence of clinical benefit without rash. Oncologist 2005; 10: 760–761.
Annals of Oncology 26: 47–57, 2015 doi:10.1093/annonc/mdu225 Published online 5 August 2014
Estimates of benefits and harms of prophylactic use of aspirin in the general population J. Cuzick1*, M. A. Thorat1, C. Bosetti2, P. H. Brown3, J. Burn4, N. R. Cook5, L. G. Ford6, E. J. Jacobs7, J. A. Jankowski8,9, C. La Vecchia2,10, M. Law11, F. Meyskens12, P. M. Rothwell13, H. J. Senn14 & A. Umar15 1 Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK; 2Department of Epidemiology, IRCCS-Istituto di Ricerche Farmacologiche ‘Mario Negri’, Milan, Italy; 3Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, USA; 4 Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK; 5Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston; 6Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda; 7Epidemiology Research Program, American Cancer Society, Atlanta, USA; 8Centre for Biomedical Research–Translational and Stratified Medicine, Peninsula Schools of Medicine and Dentistry, Plymouth University, Plymouth; 9Centre for Digestive Diseases, Blizard Institute of Cell and Molecular Science, Queen Mary University of London, London, UK; 10Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; 11Centre for Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK; 12Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, USA; 13Stroke Prevention Research Unit, Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK; 14Tumor and Breast Center ZeTuP, St Gallen, Switzerland; 15Gastrointestinal and Other Cancers Research Group, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, USA
Received 7 February 2014; revised 14 May 2014; accepted 9 June 2014
Background: Accumulating evidence supports an effect of aspirin in reducing overall cancer incidence and mortality in the general population. We reviewed current data and assessed the benefits and harms of prophylactic use of aspirin in the general population. Methods: The effect of aspirin for site-specific cancer incidence and mortality, cardiovascular events was collated from the most recent systematic reviews. Studies identified through systematic Medline search provided data regarding harmful effects of aspirin and baseline rates of harms like gastrointestinal bleeding and peptic ulcer.
*Correspondence to: Prof. Jack Cuzick, Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Tel: +44-20-7882-3518; Fax: +44-20-7882-3890; E-mail: [email protected]
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected]
Downloaded from http://annonc.oxfordjournals.org/ at Sussex Language Institute on July 28, 2015
90. Lee SC, Srivastava RM, Lopez-Albaitero A et al. Natural killer (NK): dendritic cell (DC) cross talk induced by therapeutic monoclonal antibody triggers tumor antigen-specific T cell immunity. Immunol Res 2011; 50: 248–254. 91. Rudensky AY. Regulatory T cells and Foxp3. Immunol Rev 2011; 241: 260–268. 92. Sakaguchi S. Regulatory T cells: key controllers of immunologic self-tolerance. Cell 2000; 101: 455–458. 93. Sakaguchi S, Yamaguchi T, Nomura T et al. Regulatory T cells and immune tolerance. Cell 2008; 133: 775–787. 94. Strauss L, Bergmann C, Szczepanski M et al. A unique subset of CD4 +CD25highFoxp3+ T cells secreting interleukin-10 and transforming growth factor-beta1 mediates suppression in the tumor microenvironment. Clin Cancer Res 2007; 13: 4345–4354. 95. Mooradian DL, Purchio AF, Furcht LT. Differential effects of transforming growth factor beta 1 on the growth of poorly and highly metastatic murine melanoma cells. Cancer Res 1990; 50: 273–277. 96. Nishikawa H, Kato T, Tawara I et al. IFN-gamma controls the generation/activation of CD4+ CD25+ regulatory T cells in antitumor immune response. J Immunol 2005; 175: 4433–4440. 97. Larmonier N, Marron M, Zeng Y et al. Tumor-derived CD4(+)CD25(+) regulatory T cell suppression of dendritic cell function involves TGF-beta and IL-10. Cancer Immunol Immunother 2007; 56: 48–59.
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