- Email: [email protected]
Cytokines in head and neck cancer
Cytokine & Growth Factor Reviews 17 (2006) 141–146 www.elsevier.com/locate/cytogfr
Mini review
Cytokines in head and neck cancer Ralph Pries, Barbara Wollenberg * Department of Otorhinolaryngology, University of Schleswig-Holstein Campus Lu¨beck, Klinik fu¨r HNO, Ratzeburger Allee 160, 23538 Lu¨beck, Germany Available online 15 March 2006
Abstract Head and neck squamous cell carcinoma (HNSCC) is one of the most frequent cancers in the world. Standard treatment has only marginally improved the 5-year survival rate of patients with HNSCC in the last 40 years. Alterations in immune, inflammatory as well as angiogenetic responses within the HNSCC microenvironment play a critical role in tumor aggressiveness and its response to chemo- and radiation therapies as well as its influence on the immune system. Therefore, the better understanding of secretion and regulation pathways of immune suppressive and proangiogenic cytokines in HNSCC is essential to increase the clinical perspective of this tumor type with respect to an immunomodulatory intervention in patients with HNSCC. # 2006 Elsevier Ltd. All rights reserved. Keywords: HNSCC; Cytokines; Tumorigenesis; Immune suppression; Angiogenesis
1. Cytokines as molecular mediators Manifold intercellular communication processes rely on the secretion and recognition of cytokines, which are low molecular weight, soluble proteins that are produced by virtually all cells of the innate and adaptive immune system. The activation of cytokine-producing cells triggers them to produce specific cytokines which then bind to specific cytokine receptors on other cells and thus orchestrate a huge variety of cellular activities [1]. Generally cytokines act over short distances, within narrow time frames at very low concentrations and must therefore be produced de novo in response to an immune stimulus. They are known to possess pleiotropic as well as redundant characteristics, which means that a particular cytokine can influence various cell types as well as different cytokines can share the same function. Furthermore cytokines are able to function in an antagonistic or synergistic manner by inhibiting or stimulating particular functions of other cytokines, respectively. Thus, a highly complex network of cytokine interactions exists in vivo [2]. Cytokines that * Corresponding author. Tel.: +49 451 500 2241; fax: +49 451 500 2249. E-mail address: [email protected] (B. Wollenberg). 1359-6101/$ – see front matter # 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.cytogfr.2006.02.001
regulate innate immune responses are predominantly produced by mononuclear cells such as macrophages and dendritic cells in response to so called pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharides, peptidoglycan monomers, teichoic acids, or double-stranded RNA. Therefore, cytokines are essential factors to promote and control early immune responses against inflammations and infections [1,3]. Chemokines such as IL-8, MIP-1b, or RANTES resemble a subgroup of cytokines which coordinate leukocyte migration from the blood to the site of inflammation as well as cellular trafficking through the lymph nodes and the spleen [4–6]. They upregulate the affinity of leukocyte-integrins for ligands on the vascular wall, regulate actin-polymerization processes for cellular movement and migration, and act as chemoattractants. Chemokines are produced by various cell types including leukocytes, endothelial cells, epithelial cells, and fibroblasts and dysregulation of chemokines often is responsible for disorders of the immune system such as asthma or rheumatoid arthritis [7–9]. Cells of head and neck squamous cell carcinoma (HNSCC) develop molecular strategies in order to evade growth inhibitory effects of cytokines present in the tumor microenvironment. Therefore, the malignant transformation
142
R. Pries, B. Wollenberg / Cytokine & Growth Factor Reviews 17 (2006) 141–146
process is strongly associated with an altered response to cytokine stimulation [10].
2. Cytokines in head and neck cancer Appropriate immune responses are determined by distinct molecular parameters such as the manner of antigen presentation, the amount of antigen, the species of the antigen presenting cell, individual genetic predispositions or the cytokine profile of the surrounding environment. The HNSCC microenvironment results in massively affected immune functions on distinct levels. Tumor induced or spontaneous production of numerous immune suppressive mediators contributes to these immune dysfunctions [11]. Investigations with primary cultures of human HNSCC cells indicated high secretion levels of numerous cytokines involved in indirect modulation mechanisms of immune responses and proangiogenic processes [12]. Prominent HNSCC-derived cytokines are interleukin-4 (IL-4), IL-6, IL-8, IL-10, granulocyte macrophage-colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), prostaglandin E2 (PGE2) as well as basic fibroblast growth factor (bFGF) [12–15]. HNSCC relevant cytokines and their functions are summarized in Table 1. 2.1. Angiogenesis and metastasis Angiogenesis has been linked to increased metastasis formation and decreased survival of patients with HNSCC [16,17]. Expression profiling of various angiogenic growth factors revealed that VEGF, PDGF-a/b (platelet-derived growth factor) and less frequently GM-CSF were present in high amounts in the supernatant of primary HNSCC cultures [18]. In head and neck cancer angiogenesis is significantly triggered by vascular endothelial growth factor (VEGF), IL-8 and fibroblast growth factors (FGF) [19,20]. Correspondingly, increased rates of lymph node metastasis have
been associated with the expression of the VEGF family members VEGF-A and VEGF-C [21]. Recently, macrophage migration inhibitory factor (MIF) has been shown to be expressed to various extents in HNSCC tissue specimens. MIF is a proinflammatory cytokine which is known to act as a tumor growth regulator. Although the precise role of MIF in HNSCC tumorigenesis still has to be elucidated, recent studies suggest that patients with an intratumoral MIF expression have a better prognosis compared to patients with MIF-negative tumors [22]. Hepatocyte growth factor/scatter factor (HGF) can as well be found in elevated concentrations in serum or tumor tissue of HNSCC. Recent data suggest that HGF contributes to the expression of angiogenesis factors PDGF and VEGF via an activation of the transcriptional activator Egr-1 (early growth response-1) [23]. 2.2. Immunomodulation in HNSCC Since human solid tumor tissues are known to be infiltrated by various kinds of immune cells it has to be distinguished between directly tumor-derived cytokines and cytokines produced by tumor stimulated immune cells, respectively [24–26]. Investigations on tumor tissue homogenates resulted in an IL-1 detection in all analyzed samples, whereas no significant levels of IL-1 could be measured in supernatants of short-term primary cultures of HNSCC. These supernatants also revealed lower levels of IL-4, IL-6, and GM-CSF compared to the analyzed tissue homogenates [12]. Stimulation of these primary HNSCC cultures with exogenous IL-1 resulted in significantly increased levels of IL-4, IL-6, and GM-CSF which strongly suggests that cells of HNSCC secrete cytokines not only to inhibit but to trigger local immune cells such as dendritic cells to secrete tumor promoting cytokines. IL-1 seems to play a crucial role in the regulation of cytokine production by tumor and resident tissue cells [12]. IL-1 is produced by monocytes, macrophages, dendritic cells, and various other cells and in HNSCC IL-1a and
Table 1 HNSCC relevant cytokines and their proposed cellular functions Cytokines
Sites of action
Basic fibroblast growth factor (bFGF) Granulocyte macrophage-colony-stimulating factor (GM-CSF) IL-1 IL-4 IL-6 IL-8 IL-10 Hepatocyte growth factor (HGF) Macrophage migration inhibitory factor (MIF) Platelet-derived growth factor (PDGF) Prostaglandin E2 (PGE2) Transformig growth factor-b (TGF-b) Vascular endothelial growth factor (VEGF)
Angiogenesis, metastasis CD34 mobilisation, immune suppression Cytokine secretion, gelantine production Immune suppression Inflammation regulation, anti-apoptosis Angiogenesis Immune suppression Angiogenesis Growth regulation Angiogenesis Immune suppression Immune suppression Angiogenesis, metastasis, chemoattraction
R. Pries, B. Wollenberg / Cytokine & Growth Factor Reviews 17 (2006) 141–146
IL-1b have also been demonstrated to modestly induce the production of gelantines, which are family members of the matrix metalloproteinases (MMPs) and contribute to tumor invasion and metastasis [27]. IL-1a was furthermore identified to promote the transcriptional activator NF-kB which is known to participate in various aspects of cancer induction and maintenance. IL-1a-mediated activation of transcription factor AP-1 leads to an increased expression of IL-8 in HNSCC and thus participates in the stimulation of angiogenic processes [28]. Investigations concerning a quantitative comparison of stromal growth factors like transforming growth factor a (TGF-a), TGF-b, hepatocyte growth factor (HGF), plateletderived growth factor-a (PDGF-a), insulin-like growth factor-II (IGF-II) or VEGF in tumor-associated stroma revealed that among these factors only TGF-b was significantly overexpressed [29,30]. TGF-b is known to inhibit the proliferation and function of T- and Blymphocytes as well as the function of macrophages [12,13]. High expression levels of PGE2 have been detected in HNSCC as well as in its surrounding mucosa and were shown to have a significant impact on tumor growth [31]. PGE2 is regularly produced by cells of HNSCC and interferes with monocyte functions such as migration and adherence to endothelial cells [13,32]. In addition, dendritic cells were found to produce decreased levels of IL-12 in response to tumor-derived IL-10 or PGE2 which preferentially results in the stimulation of TH2 immune responses [33]. Correspondingly, it has been shown that reduced levels of PGE2 result in decreased immune inhibitory effects that are mediated by tumor-derived prostaglandins [34]. For HNSCC GM-CSF was shown to trigger the mobilization of CD34 natural suppressor cells in the bone marrow and that vascular endothelial cell growth factor (VEGF) then triggers the chemoattraction of mobilized CD34 cells into the tumor [35,36]. These CD34 progenitor cells are able to restrict the function of HNSCC infiltrating T-cells [37], whereas their suppressive character has been suggested to act through the production of nitric oxide (NO) as well as TGF-b [38,39]. In addition, tumor-derived VEGF has been shown to participate in the blockage of dendritic cell maturation [35,40,41]. Since TH1- and TH2-related cytokines act antagonistically, this classification is useful to characterize various HNSCC cytokine regulatory routes as well as to understand their biological significance. 2.2.1. TH1 cytokines in HNSCC TH1 cytokines such as IFN-g, IL-2, and IL-12 are predominantly known to stimulate cellular immune responses. Decreased levels of TH1 cytokines have been observed in patients with HNSCC [42]. Interferons (IFN) modulate the activity of virtually every component of the immune system, whereas IFN-g is the only type II interferon besides more than 20 type I interferons such as IFN-a, IFN-b, or IFN-s. IFN-g is
143
produced by activated T-lymphocytes as part of an immune response and functions mainly to promote the activity of various components of the cell-mediated immune system such as cytotoxic T-lymphocytes (CTLs), macrophages, and natural killer (NK) cells. In addition, IFN-g is known to induce the production of MHC-I/II and co-stimulatory molecules by antigen presenting cells (APCs) in order to promote the cell-mediated immunity. In head and neck squamous cell carcinoma IFN-g was recently shown to downregulate the expression of receptor CXCR4 which plays a crucial role in tumor cell migration and metastasis [43,44]. Cytokine analysis in patients with HNSCC revealed strongly decreased levels of IFN-g as well as of plasma IL-12 in these patients [45]. IL-12 is a key inducer of TH1-associated inflammatory responses and acts protective against intracellular infections and cancer. Furthermore IL12 is known to increase the cytotoxicity and IFN-g synthesis of T-lymphocytes and NK cells [45,46]. It has been shown that macrophages and dendritic cells produced diminished levels of IL-12 in response to tumor-derived IL-10 or PGE2 [47,48]. Extended investigations concerning the secretion of cytokines known to be involved in proinflammatory and immunoregulatory processes did not reveal significant secretion levels of cytokines IL-2 and IL-12 in the analyzed HNSCC cell lines. These findings suggest that the downregulation of TH1 cytokines such as IFN-g, IL-2, and IL-12 represents a significant parameter of HNSCC immune escape mechanisms [13]. Correspondingly, recombinant IL-2 protein has shown many immunostimulatory effects in a variety of human tumors and there has been evidence for an activation of immune cells by peritumoral injections of IL-2 in patients with advanced HNSCC [49–51]. In addition, HNSCC cell lines have recently been demonstrated to express IL-18 which is a proinflammatory cytokine that plays an important role in NK cell activation and Th1 cell response. However, IL-18 was expressed intracellularly and predominantly released as an unprocessed inactive 24-kDa form [52]. 2.2.2. TH2 cytokines in HNSCC Recent data suggest a partial TH2 cytokine bias in HNSCC patients and a more aberrant expression of cytokine expression in the plasma of patients with an advanced disease. These patients reveal increased levels of TH2 cytokines IL-4, IL-6, IL-10, and GM-CSF [42,53,54]. It has also been shown that tumor infiltrating T cells were skewed toward a TH2 cytokine profile [55]. Elevated levels of cytokines IL-6 and IL-8 could as well be detected in the serum of patients with HNSCC but not in benign squamous papilloma [13]. In cells of oral squamous carcinoma the constitutive expression of cytokines IL-6 and GM-CSF has been found to be responsible for a down-regulation of the co-stimulatory molecule CD80 [54]. Traditionally, IL-6 is produced by various cells such as T-lymphocytes, macrophages, or monocytes and involved
144
R. Pries, B. Wollenberg / Cytokine & Growth Factor Reviews 17 (2006) 141–146
in distinct cellular processes like cell differentiation, the production of acute phase proteins in the liver, the proliferation of B-lymphocytes, and the production of neutrophils [56]. IL-6 was shown to have pro- as well as antiinflammatory properties and thus dysregulation of IL-6 cytokine signalling often contributes to various kinds of cancer playing a central role as a differentiation and growth factor of tumor cells [56,57]. The secretion of IL-6 by HNSCC cell lines was shown to be significantly decreased in vitro in response to tetrahiomolybdate treatment of the cells [58]. Recently, it has been suggested that those individuals who are genetically predisposed to produce high levels of IL-6 reveal a reduced capacity to reach the extreme limits of human life, whereas individuals producing high levels of IL-10 are significantly increased among centenarians [59]. In fact, the human immune system has evolved to control pathogens and thus high levels of IL-6 or low levels of IL-10 go along with an increased pathogen resistence, whereas individuals with genetically predisposed decreased levels of IL-6 or increased levels of IL-10 might better control inflammatory responses and cancer development [59]. In HNSCC it was shown that IL-1 triggers an increased expression of cytokines IL-4, IL-6, and GM-CSF [12].
GM-CSF is a family member of the colony-stimulating factors (CSF) which promote the production of colonies of the different leukocytes in the bone marrow and enhance their activity. Other CSFs are the granulocyte-colonystimulating factor (G-CSF) and the macrophage-colonystimulating factor (M-CSF) [39]. IL-4 is known to antagonize the effects of IFN-g and thus to inhibit cell-mediated immunity [46], like various additional immunomodulatory mechanisms allow cells of HNSCC to escape an efficient immune response.
3. Concluding remarks In general, immune responses in tumor patients have been shown to be biased toward the secretion of TH2 cytokines, which prevents effective antitumor TH1 immune responses [55]. Differences of detected cytokine expression levels found by different research groups such as the presence or absence of cytokines IL-4 or IL-10 [12,13] are most likely due specific kinetics (half-life), metabolism, or binding protein modulation parameters in each individual HNSCC tumor. In addition, the precise role of various cytokines in HNSCC tumorigenesis and maintenance is yet unclear and has to be further investigated. For example,
Fig. 1. The model illustrates prominent HNSCC cytokines and their regulatory functions on tumor growth and differentiation as well as on tumor infiltrating immune cells such as B- and T-lymphocytes (B, T), natural killer cells (NK), suppressive CD34 progenitor cells (CD34), macrophages (MP), and dendritic cells (DC). Arrows and blunt arrows indicate positive or negative effects, respectively. See text for details.
R. Pries, B. Wollenberg / Cytokine & Growth Factor Reviews 17 (2006) 141–146
IL-18 was shown to be intracellularly expressed as well at the mRNA as the protein level in HNSCC, whereas it was predominantly released as an unprocessed and inactive protein with a size of about 24 kDa and thus its relevance for HNSCC is yet unclear [52]. Fig. 1 illustrates a model of proposed cytokine regulatory routes in HNSCC. The understanding of these molecular networks is a fundamental step for the development of novel promising immunotherapeutic strategies against HNSCC.
Acknowledgments The authors would like to acknowledge and thank the following funding bodies: Mildred Scheel-Stiftung (Deutsche Krebshilfe), the Monika Kutzner Stiftung, the Werner and Klara Kreitz Stiftung, and the Rudolf Bartling Stiftung.
References [1] Robinson SC, Coussens LM. Soluble mediators of inflammation during tumor development. Adv Cancer Res 2005;93:159–87. [2] Rakesh K, Agrawal DK. Controlling cytokine signaling by constitutive inhibitors. Biochem Pharmacol 2005. [3] Eccles SA. Targeting key steps in metastatic tumour progression. Curr Opin Genet Dev 2005;15:77–86. [4] Coelho AL, Hogaboam CM, Kunkel SL. Chemokines provide the sustained inflammatory bridge between innate and acquired immunity. Cytokine Growth Factor Rev 2005. [5] Kim CH. The greater chemotactic network for lymphocyte trafficking: chemokines and beyond. Curr Opin Hematol 2005;12:298–304. [6] Sozzani S. Dendritic cell trafficking: more than just chemokines. Cytokine Growth Factor Rev 2005. [7] Bendall L. Chemokines and their receptors in disease. Histol Histopathol 2005;20:907–26. [8] D’Ambrosio D. Targeting chemoattractant receptors in allergic inflammation. Curr Drug Targets Inflamm Allergy 2005;4:163–7. [9] Scott K, Bradding P. Human mast cell chemokines receptors: implications for mast cell tissue localization in asthma. Clin Exp Allergy 2005;35:693–7. [10] Douglas WG, Tracy E, Tan D, et al. Development of head and neck squamous cell carcinoma is associated with altered cytokine responsiveness. Mol Cancer Res 2004;2:585–93. [11] Chin D, Boyle GM, Theile DR, Parsons PG, Coman WB. Molecular introduction to head and neck cancer (HNSCC) carcinogenesis. Br J Plast Surg 2004;57:595–602. [12] Mann EA, Spiro JD, Chen LL, Kreutzer DL. Cytokine expression by head and neck squamous cell carcinomas. Am J Surg 1992;164:567–73. [13] Chen Z, Malhotra PS, Thomas GR, et al. Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer. Clin Cancer Res 1999;5:1369–79. [14] Woods KV, El-Naggar A, Clayman GL, Grimm EA. Variable expression of cytokines in human head and neck squamous cell carcinoma cell lines and consistent expression in surgical specimens. Cancer Res 1998;58:3132–41. [15] Eisma RJ, Spiro JD, Kreutzer DL. Vascular endothelial growth factor expression in head and neck squamous cell carcinoma. Am J Surg 1997;174:513–7. [16] Sauter ER, Nesbit M, Watson JC, Klein-Szanto A, Litwin S, Herlyn M. Vascular endothelial growth factor is a marker of tumor invasion and metastasis in squamous cell carcinomas of the head and neck. Clin Cancer Res 1999;5:775–82.
145
[17] Smith BD, Smith GL, Carter D, Sasaki CT, Haffty BG. Prognostic significance of vascular endothelial growth factor protein levels in oral and oropharyngeal squamous cell carcinoma. J Clin Oncol 2000;18:2046–52. [18] Ninck S, Reisser C, Dyckhoff G, Helmke B, Bauer H, Herold-Mende C. Expression profiles of angiogenic growth factors in squamous cell carcinomas of the head and neck. Int J Cancer 2003;106:34–44. [19] Bancroft CC, Chen Z, Dong G, et al. Coexpression of proangiogenic factors IL-8 and VEGF by human head and neck squamous cell carcinoma involves coactivation by MEK-MAPK and IKK-NF-kappaB signal pathways. Clin Cancer Res 2001;7:435–42. [20] Riedel F, Gotte K, Bergler W, Rojas W, Hormann K. Expression of basic fibroblast growth factor protein and its down-regulation by interferons in head and neck cancer. Head Neck 2000;22:183–9. [21] P OC, Rhys-Evans P, Eccles SA. Expression of vascular endothelial growth factor family members in head and neck squamous cell carcinoma correlates with lymph node metastasis. Cancer 2001;92:556–68. [22] Suzuki F, Nakamaru Y, Oridate N, et al. Prognostic significance of cytoplasmic macrophage migration inhibitory factor expression in patients with squamous cell carcinoma of the head and neck treated with concurrent chemoradiotherapy. Oncol Rep 2005;13:59–64. [23] Worden B, Yang XP, Lee TL, et al. Hepatocyte growth factor/scatter factor differentially regulates expression of proangiogenic factors through Egr-1 in head and neck squamous cell carcinoma. Cancer Res 2005;65:7071–80. [24] Hartmann E, Wollenberg B, Rothenfusser S, et al. Identification and functional analysis of tumor-infiltrating plasmacytoid dendritic cells in head and neck cancer. Cancer Res 2003;63:6478–87. [25] Veltri RW, Rodman SM, Maxim PE, Baseler MW, Sprinkle PM. Immune complexes, serum proteins, cell-mediated immunity, and immune regulation in patients with squamous cell carcinoma of the head and neck. Cancer 1986;57:2295–308. [26] Heimdal JH, Aarstad HJ, Olofsson J. Peripheral blood T-lymphocyte and monocyte function and survival in patients with head and neck carcinoma. Laryngoscope 2000;110:402–7. [27] Mann EA, Hibbs MS, Spiro JD, et al. Cytokine regulation of gelatinase production by head and neck squamous cell carcinoma: the role of tumor necrosis factor-alpha. Ann Otol Rhinol Laryngol 1995;104:203–9. [28] Wolf JS, Chen Z, Dong G, et al. IL (interleukin)-1alpha promotes nuclear factor-kappaB and AP-1-induced IL-8 expression, cell survival, and proliferation in head and neck squamous cell carcinomas. Clin Cancer Res 2001;7:1812–20. [29] Rosenthal E, McCrory A, Talbert M, Young G, Murphy-Ullrich J, Gladson C. Elevated expression of TGF-beta1 in head and neck cancer-associated fibroblasts. Mol Carcinog 2004;40:116–21. [30] Logullo AF, Nonogaki S, Miguel RE, et al. Transforming growth factor beta1 (TGFbeta1) expression in head and neck squamous cell carcinoma patients as related to prognosis. J Oral Pathol Med 2003;32:139–45. [31] Schuon R, Brieger J, Franke RL, Jakob R, Mann WJ. Increased PGE2 levels in nonmalignant mucosa adjacent to squamous cell carcinoma of the head and neck. ORL J Otorhinolaryngol Relat Spec 2005;67:96– 100. [32] Zeidler R, Csanady M, Gires O, Lang S, Schmitt B, Wollenberg B. Tumor cell-derived prostaglandin E2 inhibits monocyte function by interfering with CCR5 and Mac-1. FASEB J 2000;14:661–8. [33] Kalinski P, Smits HH, Schuitemaker JH, et al. IL-4 is a mediator of IL12p70 induction by human Th2 cells: reversal of polarized Th2 phenotype by dendritic cells. J Immunol 2000;165:1877–81. [34] Young MR, Dizer M. Enhancement of immune function and tumor growth inhibition by antibodies against prostaglandin E2. Immunol Commun 1983;12:11–23. [35] Young MR, Petruzzelli GJ, Kolesiak K, Achille N, Lathers DM, Gabrilovich DI. Human squamous cell carcinomas of the head and neck chemoattract immune suppressive CD34(+) progenitor cells. Hum Immunol 2001;62:332–41.
146
R. Pries, B. Wollenberg / Cytokine & Growth Factor Reviews 17 (2006) 141–146
[36] Banich JC, Kolesiak K, Young MR. Chemoattraction of CD34+ progenitor cells and dendritic cells to the site of tumor excision as the first step of an immunotherapeutic approach to target residual tumor cells. J Immunother 2003;26:31–40. [37] Young MR, Farietta T, Crayton JW. Production of nitric oxide and transforming growth factor-beta in developing and adult rat brain. Mech Ageing Dev 1995;79:115–26. [38] Angulo I, Rodriguez R, Garcia B, Medina M, Navarro J, Subiza JL. Involvement of nitric oxide in bone marrow-derived natural suppressor activity. Its dependence on IFN-gamma. J Immunol 1995; 155:15–26. [39] Young MR, Wright MA, Lozano Y, Matthews JP, Benefield J, Prechel MM. Mechanisms of immune suppression in patients with head and neck cancer: influence on the immune infiltrate of the cancer. Int J Cancer 1996;67:333–8. [40] Almand B, Clark JI, Nikitina E, et al. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol 2001;166:678–89. [41] Gabrilovich DI, Velders MP, Sotomayor EM, Kast WM. Mechanism of immune dysfunction in cancer mediated by immature Gr-1+ myeloid cells. J Immunol 2001;166:5398–406. [42] Lathers DM, Young MR. Increased aberrance of cytokine expression in plasma of patients with more advanced squamous cell carcinoma of the head and neck. Cytokine 2004;25:220–8. [43] Katayama A, Ogino T, Bandoh N, Nonaka S, Harabuchi Y. Expression of CXCR4 and its down-regulation by IFN-{gamma} in head and neck squamous cell carcinoma. Clin Cancer Res 2005;11:2937– 46. [44] Samara GJ, Lawrence DM, Chiarelli CJ, et al. CXCR4-mediated adhesion and MMP-9 secretion in head and neck squamous cell carcinoma. Cancer Lett 2004;214:231–41. [45] Sparano A, Lathers DM, Achille N, Petruzzelli GJ, Young MR. Modulation of Th1 and Th2 cytokine profiles and their association with advanced head and neck squamous cell carcinoma. Otolaryngol Head Neck Surg 2004;131:573–6. [46] Rosenzweig SD, Holland SM. Defects in the interferon-gamma and interleukin-12 pathways. Immunol Rev 2005;203:38–47. [47] Murthy PK, Dennis VA, Lasater BL, Philipp MT. Interleukin-10 modulates proinflammatory cytokines in the human monocytic cell line THP-1 stimulated with Borrelia burgdorferi lipoproteins. Infect Immun 2000;68:6663–9.
[48] Zhou L, Nazarian AA, Smale ST. Interleukin-10 inhibits interleukin12 p40 gene transcription by targeting a late event in the activation pathway. Mol Cell Biol 2004;24:2385–96. [49] Whiteside TL, Letessier E, Hirabayashi H, et al. Evidence for local and systemic activation of immune cells by peritumoral injections of interleukin 2 in patients with advanced squamous cell carcinoma of the head and neck. Cancer Res 1993;53:5654–62. [50] Cortesina G, De Stefani A, Galeazzi E, et al. Temporary regression of recurrent squamous cell carcinoma of the head and neck is achieved with a low but not with a high dose of recombinant interleukin 2 injected perilymphatically. Br J Cancer 1994;69:572–6. [51] Wollenberg B, Kastenbauer, Mundl H, et al. Gene therapy-phase I trial for primary untreated head and neck squamous cell cancer (HNSCC) UICC stage II-IV with a single intratumoral injection of hIL-2 plasmids formulated in DOTMA/Chol. Hum Gene Ther 1999;10:141–7. [52] Martone T, Bellone G, Pagano M, et al. Constitutive expression of interleukin-18 in head and neck squamous carcinoma cells. Head Neck 2004;26:494–503. [53] Young MR. Trials and tribulations of immunotherapy as a treatment option for patients with squamous cell carcinoma of the head and neck. Cancer Immunol Immunother 2004;53:375–82. [54] Thomas GR, Chen Z, Leukinova E, Van Waes C, Wen J. Cytokines IL1 alpha, IL-6, and GM-CSF constitutively secreted by oral squamous carcinoma induce down-regulation of CD80 costimulatory molecule expression: restoration by interferon gamma. Cancer Immunol Immunother 2004;53:33–40. [55] Sheu BC, Lin RH, Lien HC, Ho HN, Hsu SM, Huang SC. Predominant Th2/Tc2 polarity of tumor-infiltrating lymphocytes in human cervical cancer. J Immunol 2001;167:2972–8. [56] Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 2003;374:1–20. [57] Riedel F, Zaiss I, Herzog D, Gotte K, Naim R, Hormann K. Serum levels of interleukin-6 in patients with primary head and neck squamous cell carcinoma. Anticancer Res 2005;25:2761–5. [58] Teknos TN, Islam M, Arenberg DA, et al. The effect of tetrathiomolybdate on cytokine expression, angiogenesis, and tumor growth in squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 2005;131:204–11. [59] Caruso C, Lio D, Cavallone L, Franceschi C. Aging, longevity, inflammation, and cancer. Ann N Y Acad Sci 2004;1028:1–13.
Mini review
Cytokines in head and neck cancer Ralph Pries, Barbara Wollenberg * Department of Otorhinolaryngology, University of Schleswig-Holstein Campus Lu¨beck, Klinik fu¨r HNO, Ratzeburger Allee 160, 23538 Lu¨beck, Germany Available online 15 March 2006
Abstract Head and neck squamous cell carcinoma (HNSCC) is one of the most frequent cancers in the world. Standard treatment has only marginally improved the 5-year survival rate of patients with HNSCC in the last 40 years. Alterations in immune, inflammatory as well as angiogenetic responses within the HNSCC microenvironment play a critical role in tumor aggressiveness and its response to chemo- and radiation therapies as well as its influence on the immune system. Therefore, the better understanding of secretion and regulation pathways of immune suppressive and proangiogenic cytokines in HNSCC is essential to increase the clinical perspective of this tumor type with respect to an immunomodulatory intervention in patients with HNSCC. # 2006 Elsevier Ltd. All rights reserved. Keywords: HNSCC; Cytokines; Tumorigenesis; Immune suppression; Angiogenesis
1. Cytokines as molecular mediators Manifold intercellular communication processes rely on the secretion and recognition of cytokines, which are low molecular weight, soluble proteins that are produced by virtually all cells of the innate and adaptive immune system. The activation of cytokine-producing cells triggers them to produce specific cytokines which then bind to specific cytokine receptors on other cells and thus orchestrate a huge variety of cellular activities [1]. Generally cytokines act over short distances, within narrow time frames at very low concentrations and must therefore be produced de novo in response to an immune stimulus. They are known to possess pleiotropic as well as redundant characteristics, which means that a particular cytokine can influence various cell types as well as different cytokines can share the same function. Furthermore cytokines are able to function in an antagonistic or synergistic manner by inhibiting or stimulating particular functions of other cytokines, respectively. Thus, a highly complex network of cytokine interactions exists in vivo [2]. Cytokines that * Corresponding author. Tel.: +49 451 500 2241; fax: +49 451 500 2249. E-mail address: [email protected] (B. Wollenberg). 1359-6101/$ – see front matter # 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.cytogfr.2006.02.001
regulate innate immune responses are predominantly produced by mononuclear cells such as macrophages and dendritic cells in response to so called pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharides, peptidoglycan monomers, teichoic acids, or double-stranded RNA. Therefore, cytokines are essential factors to promote and control early immune responses against inflammations and infections [1,3]. Chemokines such as IL-8, MIP-1b, or RANTES resemble a subgroup of cytokines which coordinate leukocyte migration from the blood to the site of inflammation as well as cellular trafficking through the lymph nodes and the spleen [4–6]. They upregulate the affinity of leukocyte-integrins for ligands on the vascular wall, regulate actin-polymerization processes for cellular movement and migration, and act as chemoattractants. Chemokines are produced by various cell types including leukocytes, endothelial cells, epithelial cells, and fibroblasts and dysregulation of chemokines often is responsible for disorders of the immune system such as asthma or rheumatoid arthritis [7–9]. Cells of head and neck squamous cell carcinoma (HNSCC) develop molecular strategies in order to evade growth inhibitory effects of cytokines present in the tumor microenvironment. Therefore, the malignant transformation
142
R. Pries, B. Wollenberg / Cytokine & Growth Factor Reviews 17 (2006) 141–146
process is strongly associated with an altered response to cytokine stimulation [10].
2. Cytokines in head and neck cancer Appropriate immune responses are determined by distinct molecular parameters such as the manner of antigen presentation, the amount of antigen, the species of the antigen presenting cell, individual genetic predispositions or the cytokine profile of the surrounding environment. The HNSCC microenvironment results in massively affected immune functions on distinct levels. Tumor induced or spontaneous production of numerous immune suppressive mediators contributes to these immune dysfunctions [11]. Investigations with primary cultures of human HNSCC cells indicated high secretion levels of numerous cytokines involved in indirect modulation mechanisms of immune responses and proangiogenic processes [12]. Prominent HNSCC-derived cytokines are interleukin-4 (IL-4), IL-6, IL-8, IL-10, granulocyte macrophage-colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), prostaglandin E2 (PGE2) as well as basic fibroblast growth factor (bFGF) [12–15]. HNSCC relevant cytokines and their functions are summarized in Table 1. 2.1. Angiogenesis and metastasis Angiogenesis has been linked to increased metastasis formation and decreased survival of patients with HNSCC [16,17]. Expression profiling of various angiogenic growth factors revealed that VEGF, PDGF-a/b (platelet-derived growth factor) and less frequently GM-CSF were present in high amounts in the supernatant of primary HNSCC cultures [18]. In head and neck cancer angiogenesis is significantly triggered by vascular endothelial growth factor (VEGF), IL-8 and fibroblast growth factors (FGF) [19,20]. Correspondingly, increased rates of lymph node metastasis have
been associated with the expression of the VEGF family members VEGF-A and VEGF-C [21]. Recently, macrophage migration inhibitory factor (MIF) has been shown to be expressed to various extents in HNSCC tissue specimens. MIF is a proinflammatory cytokine which is known to act as a tumor growth regulator. Although the precise role of MIF in HNSCC tumorigenesis still has to be elucidated, recent studies suggest that patients with an intratumoral MIF expression have a better prognosis compared to patients with MIF-negative tumors [22]. Hepatocyte growth factor/scatter factor (HGF) can as well be found in elevated concentrations in serum or tumor tissue of HNSCC. Recent data suggest that HGF contributes to the expression of angiogenesis factors PDGF and VEGF via an activation of the transcriptional activator Egr-1 (early growth response-1) [23]. 2.2. Immunomodulation in HNSCC Since human solid tumor tissues are known to be infiltrated by various kinds of immune cells it has to be distinguished between directly tumor-derived cytokines and cytokines produced by tumor stimulated immune cells, respectively [24–26]. Investigations on tumor tissue homogenates resulted in an IL-1 detection in all analyzed samples, whereas no significant levels of IL-1 could be measured in supernatants of short-term primary cultures of HNSCC. These supernatants also revealed lower levels of IL-4, IL-6, and GM-CSF compared to the analyzed tissue homogenates [12]. Stimulation of these primary HNSCC cultures with exogenous IL-1 resulted in significantly increased levels of IL-4, IL-6, and GM-CSF which strongly suggests that cells of HNSCC secrete cytokines not only to inhibit but to trigger local immune cells such as dendritic cells to secrete tumor promoting cytokines. IL-1 seems to play a crucial role in the regulation of cytokine production by tumor and resident tissue cells [12]. IL-1 is produced by monocytes, macrophages, dendritic cells, and various other cells and in HNSCC IL-1a and
Table 1 HNSCC relevant cytokines and their proposed cellular functions Cytokines
Sites of action
Basic fibroblast growth factor (bFGF) Granulocyte macrophage-colony-stimulating factor (GM-CSF) IL-1 IL-4 IL-6 IL-8 IL-10 Hepatocyte growth factor (HGF) Macrophage migration inhibitory factor (MIF) Platelet-derived growth factor (PDGF) Prostaglandin E2 (PGE2) Transformig growth factor-b (TGF-b) Vascular endothelial growth factor (VEGF)
Angiogenesis, metastasis CD34 mobilisation, immune suppression Cytokine secretion, gelantine production Immune suppression Inflammation regulation, anti-apoptosis Angiogenesis Immune suppression Angiogenesis Growth regulation Angiogenesis Immune suppression Immune suppression Angiogenesis, metastasis, chemoattraction
R. Pries, B. Wollenberg / Cytokine & Growth Factor Reviews 17 (2006) 141–146
IL-1b have also been demonstrated to modestly induce the production of gelantines, which are family members of the matrix metalloproteinases (MMPs) and contribute to tumor invasion and metastasis [27]. IL-1a was furthermore identified to promote the transcriptional activator NF-kB which is known to participate in various aspects of cancer induction and maintenance. IL-1a-mediated activation of transcription factor AP-1 leads to an increased expression of IL-8 in HNSCC and thus participates in the stimulation of angiogenic processes [28]. Investigations concerning a quantitative comparison of stromal growth factors like transforming growth factor a (TGF-a), TGF-b, hepatocyte growth factor (HGF), plateletderived growth factor-a (PDGF-a), insulin-like growth factor-II (IGF-II) or VEGF in tumor-associated stroma revealed that among these factors only TGF-b was significantly overexpressed [29,30]. TGF-b is known to inhibit the proliferation and function of T- and Blymphocytes as well as the function of macrophages [12,13]. High expression levels of PGE2 have been detected in HNSCC as well as in its surrounding mucosa and were shown to have a significant impact on tumor growth [31]. PGE2 is regularly produced by cells of HNSCC and interferes with monocyte functions such as migration and adherence to endothelial cells [13,32]. In addition, dendritic cells were found to produce decreased levels of IL-12 in response to tumor-derived IL-10 or PGE2 which preferentially results in the stimulation of TH2 immune responses [33]. Correspondingly, it has been shown that reduced levels of PGE2 result in decreased immune inhibitory effects that are mediated by tumor-derived prostaglandins [34]. For HNSCC GM-CSF was shown to trigger the mobilization of CD34 natural suppressor cells in the bone marrow and that vascular endothelial cell growth factor (VEGF) then triggers the chemoattraction of mobilized CD34 cells into the tumor [35,36]. These CD34 progenitor cells are able to restrict the function of HNSCC infiltrating T-cells [37], whereas their suppressive character has been suggested to act through the production of nitric oxide (NO) as well as TGF-b [38,39]. In addition, tumor-derived VEGF has been shown to participate in the blockage of dendritic cell maturation [35,40,41]. Since TH1- and TH2-related cytokines act antagonistically, this classification is useful to characterize various HNSCC cytokine regulatory routes as well as to understand their biological significance. 2.2.1. TH1 cytokines in HNSCC TH1 cytokines such as IFN-g, IL-2, and IL-12 are predominantly known to stimulate cellular immune responses. Decreased levels of TH1 cytokines have been observed in patients with HNSCC [42]. Interferons (IFN) modulate the activity of virtually every component of the immune system, whereas IFN-g is the only type II interferon besides more than 20 type I interferons such as IFN-a, IFN-b, or IFN-s. IFN-g is
143
produced by activated T-lymphocytes as part of an immune response and functions mainly to promote the activity of various components of the cell-mediated immune system such as cytotoxic T-lymphocytes (CTLs), macrophages, and natural killer (NK) cells. In addition, IFN-g is known to induce the production of MHC-I/II and co-stimulatory molecules by antigen presenting cells (APCs) in order to promote the cell-mediated immunity. In head and neck squamous cell carcinoma IFN-g was recently shown to downregulate the expression of receptor CXCR4 which plays a crucial role in tumor cell migration and metastasis [43,44]. Cytokine analysis in patients with HNSCC revealed strongly decreased levels of IFN-g as well as of plasma IL-12 in these patients [45]. IL-12 is a key inducer of TH1-associated inflammatory responses and acts protective against intracellular infections and cancer. Furthermore IL12 is known to increase the cytotoxicity and IFN-g synthesis of T-lymphocytes and NK cells [45,46]. It has been shown that macrophages and dendritic cells produced diminished levels of IL-12 in response to tumor-derived IL-10 or PGE2 [47,48]. Extended investigations concerning the secretion of cytokines known to be involved in proinflammatory and immunoregulatory processes did not reveal significant secretion levels of cytokines IL-2 and IL-12 in the analyzed HNSCC cell lines. These findings suggest that the downregulation of TH1 cytokines such as IFN-g, IL-2, and IL-12 represents a significant parameter of HNSCC immune escape mechanisms [13]. Correspondingly, recombinant IL-2 protein has shown many immunostimulatory effects in a variety of human tumors and there has been evidence for an activation of immune cells by peritumoral injections of IL-2 in patients with advanced HNSCC [49–51]. In addition, HNSCC cell lines have recently been demonstrated to express IL-18 which is a proinflammatory cytokine that plays an important role in NK cell activation and Th1 cell response. However, IL-18 was expressed intracellularly and predominantly released as an unprocessed inactive 24-kDa form [52]. 2.2.2. TH2 cytokines in HNSCC Recent data suggest a partial TH2 cytokine bias in HNSCC patients and a more aberrant expression of cytokine expression in the plasma of patients with an advanced disease. These patients reveal increased levels of TH2 cytokines IL-4, IL-6, IL-10, and GM-CSF [42,53,54]. It has also been shown that tumor infiltrating T cells were skewed toward a TH2 cytokine profile [55]. Elevated levels of cytokines IL-6 and IL-8 could as well be detected in the serum of patients with HNSCC but not in benign squamous papilloma [13]. In cells of oral squamous carcinoma the constitutive expression of cytokines IL-6 and GM-CSF has been found to be responsible for a down-regulation of the co-stimulatory molecule CD80 [54]. Traditionally, IL-6 is produced by various cells such as T-lymphocytes, macrophages, or monocytes and involved
144
R. Pries, B. Wollenberg / Cytokine & Growth Factor Reviews 17 (2006) 141–146
in distinct cellular processes like cell differentiation, the production of acute phase proteins in the liver, the proliferation of B-lymphocytes, and the production of neutrophils [56]. IL-6 was shown to have pro- as well as antiinflammatory properties and thus dysregulation of IL-6 cytokine signalling often contributes to various kinds of cancer playing a central role as a differentiation and growth factor of tumor cells [56,57]. The secretion of IL-6 by HNSCC cell lines was shown to be significantly decreased in vitro in response to tetrahiomolybdate treatment of the cells [58]. Recently, it has been suggested that those individuals who are genetically predisposed to produce high levels of IL-6 reveal a reduced capacity to reach the extreme limits of human life, whereas individuals producing high levels of IL-10 are significantly increased among centenarians [59]. In fact, the human immune system has evolved to control pathogens and thus high levels of IL-6 or low levels of IL-10 go along with an increased pathogen resistence, whereas individuals with genetically predisposed decreased levels of IL-6 or increased levels of IL-10 might better control inflammatory responses and cancer development [59]. In HNSCC it was shown that IL-1 triggers an increased expression of cytokines IL-4, IL-6, and GM-CSF [12].
GM-CSF is a family member of the colony-stimulating factors (CSF) which promote the production of colonies of the different leukocytes in the bone marrow and enhance their activity. Other CSFs are the granulocyte-colonystimulating factor (G-CSF) and the macrophage-colonystimulating factor (M-CSF) [39]. IL-4 is known to antagonize the effects of IFN-g and thus to inhibit cell-mediated immunity [46], like various additional immunomodulatory mechanisms allow cells of HNSCC to escape an efficient immune response.
3. Concluding remarks In general, immune responses in tumor patients have been shown to be biased toward the secretion of TH2 cytokines, which prevents effective antitumor TH1 immune responses [55]. Differences of detected cytokine expression levels found by different research groups such as the presence or absence of cytokines IL-4 or IL-10 [12,13] are most likely due specific kinetics (half-life), metabolism, or binding protein modulation parameters in each individual HNSCC tumor. In addition, the precise role of various cytokines in HNSCC tumorigenesis and maintenance is yet unclear and has to be further investigated. For example,
Fig. 1. The model illustrates prominent HNSCC cytokines and their regulatory functions on tumor growth and differentiation as well as on tumor infiltrating immune cells such as B- and T-lymphocytes (B, T), natural killer cells (NK), suppressive CD34 progenitor cells (CD34), macrophages (MP), and dendritic cells (DC). Arrows and blunt arrows indicate positive or negative effects, respectively. See text for details.
R. Pries, B. Wollenberg / Cytokine & Growth Factor Reviews 17 (2006) 141–146
IL-18 was shown to be intracellularly expressed as well at the mRNA as the protein level in HNSCC, whereas it was predominantly released as an unprocessed and inactive protein with a size of about 24 kDa and thus its relevance for HNSCC is yet unclear [52]. Fig. 1 illustrates a model of proposed cytokine regulatory routes in HNSCC. The understanding of these molecular networks is a fundamental step for the development of novel promising immunotherapeutic strategies against HNSCC.
Acknowledgments The authors would like to acknowledge and thank the following funding bodies: Mildred Scheel-Stiftung (Deutsche Krebshilfe), the Monika Kutzner Stiftung, the Werner and Klara Kreitz Stiftung, and the Rudolf Bartling Stiftung.
References [1] Robinson SC, Coussens LM. Soluble mediators of inflammation during tumor development. Adv Cancer Res 2005;93:159–87. [2] Rakesh K, Agrawal DK. Controlling cytokine signaling by constitutive inhibitors. Biochem Pharmacol 2005. [3] Eccles SA. Targeting key steps in metastatic tumour progression. Curr Opin Genet Dev 2005;15:77–86. [4] Coelho AL, Hogaboam CM, Kunkel SL. Chemokines provide the sustained inflammatory bridge between innate and acquired immunity. Cytokine Growth Factor Rev 2005. [5] Kim CH. The greater chemotactic network for lymphocyte trafficking: chemokines and beyond. Curr Opin Hematol 2005;12:298–304. [6] Sozzani S. Dendritic cell trafficking: more than just chemokines. Cytokine Growth Factor Rev 2005. [7] Bendall L. Chemokines and their receptors in disease. Histol Histopathol 2005;20:907–26. [8] D’Ambrosio D. Targeting chemoattractant receptors in allergic inflammation. Curr Drug Targets Inflamm Allergy 2005;4:163–7. [9] Scott K, Bradding P. Human mast cell chemokines receptors: implications for mast cell tissue localization in asthma. Clin Exp Allergy 2005;35:693–7. [10] Douglas WG, Tracy E, Tan D, et al. Development of head and neck squamous cell carcinoma is associated with altered cytokine responsiveness. Mol Cancer Res 2004;2:585–93. [11] Chin D, Boyle GM, Theile DR, Parsons PG, Coman WB. Molecular introduction to head and neck cancer (HNSCC) carcinogenesis. Br J Plast Surg 2004;57:595–602. [12] Mann EA, Spiro JD, Chen LL, Kreutzer DL. Cytokine expression by head and neck squamous cell carcinomas. Am J Surg 1992;164:567–73. [13] Chen Z, Malhotra PS, Thomas GR, et al. Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer. Clin Cancer Res 1999;5:1369–79. [14] Woods KV, El-Naggar A, Clayman GL, Grimm EA. Variable expression of cytokines in human head and neck squamous cell carcinoma cell lines and consistent expression in surgical specimens. Cancer Res 1998;58:3132–41. [15] Eisma RJ, Spiro JD, Kreutzer DL. Vascular endothelial growth factor expression in head and neck squamous cell carcinoma. Am J Surg 1997;174:513–7. [16] Sauter ER, Nesbit M, Watson JC, Klein-Szanto A, Litwin S, Herlyn M. Vascular endothelial growth factor is a marker of tumor invasion and metastasis in squamous cell carcinomas of the head and neck. Clin Cancer Res 1999;5:775–82.
145
[17] Smith BD, Smith GL, Carter D, Sasaki CT, Haffty BG. Prognostic significance of vascular endothelial growth factor protein levels in oral and oropharyngeal squamous cell carcinoma. J Clin Oncol 2000;18:2046–52. [18] Ninck S, Reisser C, Dyckhoff G, Helmke B, Bauer H, Herold-Mende C. Expression profiles of angiogenic growth factors in squamous cell carcinomas of the head and neck. Int J Cancer 2003;106:34–44. [19] Bancroft CC, Chen Z, Dong G, et al. Coexpression of proangiogenic factors IL-8 and VEGF by human head and neck squamous cell carcinoma involves coactivation by MEK-MAPK and IKK-NF-kappaB signal pathways. Clin Cancer Res 2001;7:435–42. [20] Riedel F, Gotte K, Bergler W, Rojas W, Hormann K. Expression of basic fibroblast growth factor protein and its down-regulation by interferons in head and neck cancer. Head Neck 2000;22:183–9. [21] P OC, Rhys-Evans P, Eccles SA. Expression of vascular endothelial growth factor family members in head and neck squamous cell carcinoma correlates with lymph node metastasis. Cancer 2001;92:556–68. [22] Suzuki F, Nakamaru Y, Oridate N, et al. Prognostic significance of cytoplasmic macrophage migration inhibitory factor expression in patients with squamous cell carcinoma of the head and neck treated with concurrent chemoradiotherapy. Oncol Rep 2005;13:59–64. [23] Worden B, Yang XP, Lee TL, et al. Hepatocyte growth factor/scatter factor differentially regulates expression of proangiogenic factors through Egr-1 in head and neck squamous cell carcinoma. Cancer Res 2005;65:7071–80. [24] Hartmann E, Wollenberg B, Rothenfusser S, et al. Identification and functional analysis of tumor-infiltrating plasmacytoid dendritic cells in head and neck cancer. Cancer Res 2003;63:6478–87. [25] Veltri RW, Rodman SM, Maxim PE, Baseler MW, Sprinkle PM. Immune complexes, serum proteins, cell-mediated immunity, and immune regulation in patients with squamous cell carcinoma of the head and neck. Cancer 1986;57:2295–308. [26] Heimdal JH, Aarstad HJ, Olofsson J. Peripheral blood T-lymphocyte and monocyte function and survival in patients with head and neck carcinoma. Laryngoscope 2000;110:402–7. [27] Mann EA, Hibbs MS, Spiro JD, et al. Cytokine regulation of gelatinase production by head and neck squamous cell carcinoma: the role of tumor necrosis factor-alpha. Ann Otol Rhinol Laryngol 1995;104:203–9. [28] Wolf JS, Chen Z, Dong G, et al. IL (interleukin)-1alpha promotes nuclear factor-kappaB and AP-1-induced IL-8 expression, cell survival, and proliferation in head and neck squamous cell carcinomas. Clin Cancer Res 2001;7:1812–20. [29] Rosenthal E, McCrory A, Talbert M, Young G, Murphy-Ullrich J, Gladson C. Elevated expression of TGF-beta1 in head and neck cancer-associated fibroblasts. Mol Carcinog 2004;40:116–21. [30] Logullo AF, Nonogaki S, Miguel RE, et al. Transforming growth factor beta1 (TGFbeta1) expression in head and neck squamous cell carcinoma patients as related to prognosis. J Oral Pathol Med 2003;32:139–45. [31] Schuon R, Brieger J, Franke RL, Jakob R, Mann WJ. Increased PGE2 levels in nonmalignant mucosa adjacent to squamous cell carcinoma of the head and neck. ORL J Otorhinolaryngol Relat Spec 2005;67:96– 100. [32] Zeidler R, Csanady M, Gires O, Lang S, Schmitt B, Wollenberg B. Tumor cell-derived prostaglandin E2 inhibits monocyte function by interfering with CCR5 and Mac-1. FASEB J 2000;14:661–8. [33] Kalinski P, Smits HH, Schuitemaker JH, et al. IL-4 is a mediator of IL12p70 induction by human Th2 cells: reversal of polarized Th2 phenotype by dendritic cells. J Immunol 2000;165:1877–81. [34] Young MR, Dizer M. Enhancement of immune function and tumor growth inhibition by antibodies against prostaglandin E2. Immunol Commun 1983;12:11–23. [35] Young MR, Petruzzelli GJ, Kolesiak K, Achille N, Lathers DM, Gabrilovich DI. Human squamous cell carcinomas of the head and neck chemoattract immune suppressive CD34(+) progenitor cells. Hum Immunol 2001;62:332–41.
146
R. Pries, B. Wollenberg / Cytokine & Growth Factor Reviews 17 (2006) 141–146
[36] Banich JC, Kolesiak K, Young MR. Chemoattraction of CD34+ progenitor cells and dendritic cells to the site of tumor excision as the first step of an immunotherapeutic approach to target residual tumor cells. J Immunother 2003;26:31–40. [37] Young MR, Farietta T, Crayton JW. Production of nitric oxide and transforming growth factor-beta in developing and adult rat brain. Mech Ageing Dev 1995;79:115–26. [38] Angulo I, Rodriguez R, Garcia B, Medina M, Navarro J, Subiza JL. Involvement of nitric oxide in bone marrow-derived natural suppressor activity. Its dependence on IFN-gamma. J Immunol 1995; 155:15–26. [39] Young MR, Wright MA, Lozano Y, Matthews JP, Benefield J, Prechel MM. Mechanisms of immune suppression in patients with head and neck cancer: influence on the immune infiltrate of the cancer. Int J Cancer 1996;67:333–8. [40] Almand B, Clark JI, Nikitina E, et al. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol 2001;166:678–89. [41] Gabrilovich DI, Velders MP, Sotomayor EM, Kast WM. Mechanism of immune dysfunction in cancer mediated by immature Gr-1+ myeloid cells. J Immunol 2001;166:5398–406. [42] Lathers DM, Young MR. Increased aberrance of cytokine expression in plasma of patients with more advanced squamous cell carcinoma of the head and neck. Cytokine 2004;25:220–8. [43] Katayama A, Ogino T, Bandoh N, Nonaka S, Harabuchi Y. Expression of CXCR4 and its down-regulation by IFN-{gamma} in head and neck squamous cell carcinoma. Clin Cancer Res 2005;11:2937– 46. [44] Samara GJ, Lawrence DM, Chiarelli CJ, et al. CXCR4-mediated adhesion and MMP-9 secretion in head and neck squamous cell carcinoma. Cancer Lett 2004;214:231–41. [45] Sparano A, Lathers DM, Achille N, Petruzzelli GJ, Young MR. Modulation of Th1 and Th2 cytokine profiles and their association with advanced head and neck squamous cell carcinoma. Otolaryngol Head Neck Surg 2004;131:573–6. [46] Rosenzweig SD, Holland SM. Defects in the interferon-gamma and interleukin-12 pathways. Immunol Rev 2005;203:38–47. [47] Murthy PK, Dennis VA, Lasater BL, Philipp MT. Interleukin-10 modulates proinflammatory cytokines in the human monocytic cell line THP-1 stimulated with Borrelia burgdorferi lipoproteins. Infect Immun 2000;68:6663–9.
[48] Zhou L, Nazarian AA, Smale ST. Interleukin-10 inhibits interleukin12 p40 gene transcription by targeting a late event in the activation pathway. Mol Cell Biol 2004;24:2385–96. [49] Whiteside TL, Letessier E, Hirabayashi H, et al. Evidence for local and systemic activation of immune cells by peritumoral injections of interleukin 2 in patients with advanced squamous cell carcinoma of the head and neck. Cancer Res 1993;53:5654–62. [50] Cortesina G, De Stefani A, Galeazzi E, et al. Temporary regression of recurrent squamous cell carcinoma of the head and neck is achieved with a low but not with a high dose of recombinant interleukin 2 injected perilymphatically. Br J Cancer 1994;69:572–6. [51] Wollenberg B, Kastenbauer, Mundl H, et al. Gene therapy-phase I trial for primary untreated head and neck squamous cell cancer (HNSCC) UICC stage II-IV with a single intratumoral injection of hIL-2 plasmids formulated in DOTMA/Chol. Hum Gene Ther 1999;10:141–7. [52] Martone T, Bellone G, Pagano M, et al. Constitutive expression of interleukin-18 in head and neck squamous carcinoma cells. Head Neck 2004;26:494–503. [53] Young MR. Trials and tribulations of immunotherapy as a treatment option for patients with squamous cell carcinoma of the head and neck. Cancer Immunol Immunother 2004;53:375–82. [54] Thomas GR, Chen Z, Leukinova E, Van Waes C, Wen J. Cytokines IL1 alpha, IL-6, and GM-CSF constitutively secreted by oral squamous carcinoma induce down-regulation of CD80 costimulatory molecule expression: restoration by interferon gamma. Cancer Immunol Immunother 2004;53:33–40. [55] Sheu BC, Lin RH, Lien HC, Ho HN, Hsu SM, Huang SC. Predominant Th2/Tc2 polarity of tumor-infiltrating lymphocytes in human cervical cancer. J Immunol 2001;167:2972–8. [56] Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 2003;374:1–20. [57] Riedel F, Zaiss I, Herzog D, Gotte K, Naim R, Hormann K. Serum levels of interleukin-6 in patients with primary head and neck squamous cell carcinoma. Anticancer Res 2005;25:2761–5. [58] Teknos TN, Islam M, Arenberg DA, et al. The effect of tetrathiomolybdate on cytokine expression, angiogenesis, and tumor growth in squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 2005;131:204–11. [59] Caruso C, Lio D, Cavallone L, Franceschi C. Aging, longevity, inflammation, and cancer. Ann N Y Acad Sci 2004;1028:1–13.