Links between innate and cognate tumor immunity

Links between innate and cognate tumor immunity Franc¸ois Ghiringhelli1,2, Lionel Apetoh1, Frank Housseau3, Guido Kroemer4,5,6 and Laurence Zitvogel1 Cancer results from a tumor cell intrinsic dysregulation of oncogenes, tumor suppressor and stability genes as well as from the avoidance of immunosurveillance. A complex network of cellular interactions allows one to mount cognate anti-tumor immune responses. Recently, discoveries have been made regarding the links between innate and cognate antitumor immunity eliciting protective T-cell responses. The intricate differentiation pathway, whereby dendritic cells can efficiently mature in the tumor microenvironment, appears crucial for the priming of T cells. Transformed cells might deliver danger signals directly to the dendritic cell. Alternatively, other cell types belonging to the innate immune system can sense transformed cells through a specific set of receptors and then interact with dendritic cells to modulate their activation state. A novel subset of innate effector cells called interferon-producing killer dendritic cells are multitasking chimeras that can recognize and kill transformed cells, and undergo a maturation state of antigen presentation. Also, evidence has been produced suggesting that cell death promoted by conventional chemotherapy or radiotherapy might elicit interactions between the innate and the cognate immune system that result in anti-tumor immune responses. Addresses 1 U805 Institut National de la Sante´ et de la Recherche Me´dicale, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France 2 Institut National de la Sante´ et de la Recherche Me´dicale, U517, University of Burgundy, 21079 Dijon, France 3 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine Baltimore, MD 21231, USA 4 INSERM U848, 39 rue Camille-Desmoulins, 94805 Villejuif, France 5 Institut Gustave Roussy, 39 rue Camille-Desmoulins, 94805 Villejuif, France 6 Universite´ Paris Sud—Paris 11, 39 rue Camille-Desmoulins, 94805 Villejuif, France Corresponding author: Zitvogel, Laurence ([email protected])

Current Opinion in Immunology 2007, 19:224–231 This review comes from a themed issue on Tumour immunology Edited by Mark Smyth Available online 15th February 2007 0952-7915/$ – see front matter # 2006 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coi.2007.02.003

from normal cells in antigenic terms, do not display the danger signals required for dendritic cell (DC) activation, and frequently secrete immunosuppressive factors. Activation of DCs is a crucial event in the initiation and amplification of immune responses. The term ‘DC maturation’ refers to an intricate differentiation process whereby DCs respond to environmental stimuli to elicit adaptive immune responses. Proinflammatory cytokines alone are insufficient for the induction of adaptive immunity in vivo. Additional changes can be imparted to the DC through CD40 triggering, contributing to potent T-cell immunity [1,2]. As predicted by CA Janeway Jr [3], innate immune components dictate the outcome of adaptive immune responses. This paradigm relies upon the demonstration that microbial products stimulate Toll-like receptors (TLRs) or other pathogen-recognition receptors, leading to the surface expression of costimulatory molecules, which have to be presented on the same antigen-presenting cell (APC) as the ligands for the T-cell receptor [3]. In this review, we will discuss potential TLR ligands and other ‘damage-associated molecular patterns’ (DAMPs) that are released or exposed by tumor cells, either spontaneously or in response to therapy. We postulate that such DAMPs can promote a decisive cooperation between the innate and cognate immune systems.

The cruel reality: immunosuppression resulting from the DC–tumor interaction It is clear that the tumor microenvironment can promote immune tolerance [4]. The requirement for DCs in T-cell priming is well established, however DCs are immature and dysfunctional in tumor hosts. Oncogenic signaling contributes to tumor immune evasion by inhibiting DC differentiation and maturation [5,6]. In particular, signal transducer and activator of transcription 3 (STAT3) is frequently activated in cancers and mediates immune suppression by inhibiting the expression of proinflammatory chemokines and cytokines required for DC maturation [7]. In addition, STAT3 activation in tumor cells promotes STAT3 activation in DCs and blunts their functions [8] as well as promoting the migration of immune effectors into tumor beds.

The first way to save DCs: activation of NK, NKT and gd T cells Introduction Tumor cells are often poorly immunogenic because they are derived from normal tissues and hence differ minimally Current Opinion in Immunology 2007, 19:224–231

Whereas DCs sense microbes through the TLR, alternate innate immune cells (such as natural killer cells [NK], natural killer T cells [NKT] and gd T cells) can sense www.sciencedirect.com

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transformed cells and interact with DCs to modulate their activation state. Licensing of NK cells by transformed cells that promote a DC/NK cell cross-talk

NK cells can detect changes in tumor cells in the absence of inflammatory signals and can mediate first-line tumor rejection [9]. Natural cytotoxicity receptors are the main activating receptors on human NK cells that recognize melanoma or B-cell lymphoma [10]. In both humans and mice, NKG2D recognizes a specific set of ligands expressed on the cell surface of many distinct types of transformed cells. NK cell activation can be further enhanced by lack of triggering of inhibitory receptors by MHC class I molecules. Once activated, NK cells can either kill or promote DC maturation, depending on the DC:NK cell ratio [11]. NKp30 constitutively expressed by human NK cells is the major natural cytotoxicity receptor involved in NKmediated DC activation [12]. Activated NK cells induce maturation of DCs into a stable type 1-polarized DC (DC1), which is capable of producing large amounts of IL-12p70. NK cell-mediated DC1 polarization depends on NK interferon (IFN)-g and tumor necrosis factor (TNF)-a secretion and is resistant to tumor-suppressive factors [13]. Detection of low MHC class I expression, NKG2D ligands or CD27 ligand by innate immune cells can link innate and adaptive immunity to cooperatively induce protective T-cell responses. Tumor recognition by NK cells through CD70 or NKG2D receptors leading to tumor lysis has been shown to evoke T-cell immunity against MHC class I expressing tumor cells [14]. The role for DC and the DC/NK cell cross-talk appears pivotal in this outcome. NK cell recognition of MHC class Ilow tumor targets can initiate a cascade of immune events leading to long-term T-cell memory responses. Activated NK cells prime DCs to produce IL-12 and to induce protective CD8+ T-cell responses [15,16]. Whereas NK cells can activate DCs, DCs also play a crucial role in recruitment of NK cells and in promotion of their proliferation and effector function. This was first demonstrated in a NK cell dependent mesothelioma tumor model responding to Flt3L [17]. Flt3L (Fms like tyrosine kinase ligand) is a member of a small family of cytokines acting as tyrosine kinase receptor ligands that stimulate the proliferation of primitive hematopoietic progenitors. The CD8a+ DCs were required for the Flt3L-mediated antitumor effects. DC/NK cell cocultures revealed that TNF-a-stimulated DCs could trigger NK cell cytotoxicity. These studies have been substantiated by in vivo experiments showing a recruitment of NK cells to lymph nodes (LNs) mediated by DCs responding to Th2 cytokines or TLR4 ligands [18]. Such www.sciencedirect.com

NK cell recruitment is required for IFN-g production and subsequent Th1 differentiation [19]. However, the DC/ NK cell cross-talk might be compromised by either regulatory CD4+CD25+Foxp3+ T cells [20,21] or a NK cell subset expressing c-kit and CD25 molecules [22] — both of which could be expanded as a result of tumor expansion. DC sensing of microbial products enhances NK cell functions in vitro and in vivo through mechanisms that involve IL-2, IFN-a, IL-12 and IL-15Ra/IL-15 [23–25]. In contrast, the tumor-derived signals that promote NK cell triggering by DCs are still poorly understood. Secretion of IL-18 by DCs in the synapse between interacting DCs and NK cells can promote the release of high mobility group box chromosomal protein 1 (HMGB1) from NK cells and the subsequent activation of surrounding DCs [26]. Reportedly, ligands for TLR3 or TLR9 can be released by apoptotic tumor cells and synergize with plasmacytoid DCs (pDCs) or conventional DCs to activate NK cells in the context of exogenous IL-12 or IL-8 [27]. Licensing of NKT and gd T cells by transformed cells and subsequent DC maturation

NKTs that express both NK and TCR molecules use a single Va chain to recognize microbial and endogenous glycolipids presented by non-classical MHC class I CD1d molecules [28]. In addition, NKTs can detect ganglioside GD3, which is overexpressed on melanoma cells [29]. gd T cells recognize tumor antigens — typically small pyrophosphomonoesters and alkylamines [30]. When tumor cells accumulate mevalonate metabolites in response to hydroxyl-methylglutaryl-CoA reductase overexpression or drugs they acquire the capacity to stimulate gd T cells [31]. DC maturation has been documented in vivo after NKT cell triggering using aGalCer presented on DCs [32] and after exposure to phosphoantigen-specific gd T cells [33]. CD40–CD40L interactions between aGalCer-activated NKTs and DCs prompted the efficient priming of adaptive immune responses by DCs [1]. Like NK cells, activated NKT cells license DCs towards a DC1/Th1 type of differentiation (Figure 1).

The second way to save DCs: endogenous danger signals or ‘damage-associated molecular patterns’ The innate immune system is rapidly activated and initiates an inflammatory cascade in response to infection or tissue injury. An inflammatory reaction can be triggered in a non-infectious microenvironment, because damaged cells release inflammatory mediators including cytokines, oxidized mitochondrial DNA, heat shock proteins, HMGB1, ATP and uric acid [34]. Current Opinion in Immunology 2007, 19:224–231

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Figure 1

Licensing of DCs by innate effectors or damage-associated molecular patterns for adequate T-cell responses. Activation and maturation of immature DCs are inhibited by STAT3 activity during tumor progression. Innate effectors licensed through transformed cells following recognition of defined and specific structures are able to promote DC maturation. Alternatively, endogenous danger signals such as HMGB1, ATP and uric acid released following killing of tumors by innate effectors, chemotherapy, X-rays or antibodies might contribute to DC activation. IL-18-activated NK cells can be considered as helper NK cells to elicit CD8+ T cells in lymph nodes. Help to immature DCs can also be provided by activated pDCs through CD40L.

A putative role of ATP

Extracellular nucleotides are important regulators of inflammation and immune responses [35]. Nucleotides released by regulated exocytosis or passive leakage after cell damage bind to P2 purinergic receptors expressed on murine and human DCs, thereby promoting IL-1b and TNF-a secretion [36]. ATP induces functional expression of CXCR4 and CCR7, stimulating DCs to home to LNs. However, the relevance of ATP as a danger signal during tumor insult remains unclear. Potential role of FasL

Accumulating evidence has challenged the view that FasL is the main molecule responsible for tumor Current Opinion in Immunology 2007, 19:224–231

immune escape [37]. Soluble or membrane-bound FasL-expressing cells can attract neutrophils and activate T cells [38]. The early non-specific inflammatory responses induced by FasL-expressing tumor cells promote tumor-specific cytotoxic T lymphocyte (CTL) responses and protective immunity [38]. Given the established role of neutrophils in T-cell responses [39], FasL expression on DCs promotes innate and cognate immunity. Moreover, not only are immature and mature DCs resistant to Fas-induced cell death (because of constitutive expression of Fas-associated death domain-like IL-1b converting enzyme inhibitory protein FLIP); in addition, engagement of Fas on myeloid DCs induces DC maturation, secretion of www.sciencedirect.com

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IL-1b and TNF-a, and contributes to Th1 differentiation in an IL-12-independent manner [40]. A molecular link between cell injury and immunity: uric acid

Shi et al. [41] demonstrated that uric acid is a principal endogenous danger signal released from injured cells. Uric acid was shown to stimulate DC maturation in vitro and to significantly enhance elicitation of antigen-specific CTL responses in vivo. Uric acid increased markedly after treatment with heat shock and ultraviolet radiation. It is conceivable that some chemotherapeutic apoptosis inducers could promote the release of uric acid by injured tumor cells. HMGB1: a molecular link between innate and cognate immunity

HMGB1 is a nuclear constituent and mediator of inflammation in the extracellular environment that can be released by damaged cells [42]. HMGB1 released by dead cells is a potent adjuvant in vivo. Indeed, HMGB1-binding to its receptors (advanced glycation end products, TLR2 and TLR4 [43]) promotes DC activation and elicits an antitumor immune response. HMGB1 is released during the iDC/NK cell cross-talk in an IL-18-dependent manner [26]. Importantly, CTL-, NK- or TRAIL-mediated lysis of melanoma cells promoted the tumor release of HMGB1 [44]. Therefore, HMGB1 appeared to be a protagonist of innate–cognate interactions.

The catalyzing role of cytokines IL-15

Treatment of DCs with type 1 IFN or cooperation with pDCs results in IL-15 production. IL-15 controls IL-12 production of macrophages and DCs in response to TLR4 ligands [45], and can stimulate anti-tumor immune responses in vivo [46]. Although tumorigenesis has not been studied in IL-15- or IL-15Ra-deficient mice, tumor vaccines genetically modified to encode IL-15 demonstrated the potent antitumor activity of IL-15. MC38 cells engineered to express IL-15Ra are less tumorigenic than wild-type MC38 cells. Moreover, MC38 cells fail to metastasize to the lungs of IL-15 transgenic animals. Given the role of IL-15 in DC-mediated NK cell homeostasis, NK cell activation, prevention of activationinduced cell death, and persistence of CD8+ memory T-cell responses, IL-15 can be considered to be a key cytokine for the treatment of cancer or as a component of cancer vaccines [47]. IFN type I

IFN-a provides an important link between innate and adaptive immune responses [48]. Endogenously produced IFN-a/b is required for the prevention of sarcoma outgrowth by acting directly on host bone marrow derived cells [49]. Sarcomas arising in IFN type I R / mice are highly immunogenic in wild-type animals. However, the www.sciencedirect.com

identity of the IFN type 1 producing cells that participate in host protective antitumor immunity remains unknown. Several reports associate pDC invasion in tumor beds with poor prognosis [50]. Some authors described deficiencies in pDC numbers in tumor draining lymph nodes or blood in various cancer types [51,52]. However, recent reports that analyze pDC functions in non small cell lung cancers could show normal responses of lymph node pDC to CpG oligo deoxynucleotide ex vivo [53]. Salio et al. [54] also demonstrated the capacity of IFN type I containing pDC supernatants to induce CD95 and MHC class I on melanoma cells. Whether tumor infiltrating pDCs secrete IFN type 1 in vivo remains unknown and probably depends on the engagement of CD40 or TLR9 which will trigger positive signalling. By contrast, BDCA2 receptors will trigger negative signaling [55]. If the source of IFN-a is not clear during tumor regression, the effects on type 1 IFN on conventional DCs (cDCs) can be unexpected. Exogenous type 1 IFN plays a differential role for cross-presentation on cDCs. STAT1 signaling in immature cDCs resulted in significant inhibition of CD40L-induced IL-12 production, accounting for the inhibition of CD8+ T-cell activation [56]. IFN type II

IFN-g plays a crucial role in tumor immunosurveillance, as originally stated by Schreiber and co-workers [57]. IFN-g appears to act at the level of the tumor itself to instigate antigen processing and presentation. The source of IFN-g could be gd T cells or alternate innate effectors [57,58]. When produced by activated NK cells, probably in the lymph nodes, IFN-g contributes to DC maturation and enables IL-12-dependent Th1 priming [15,16]. At the tumor site, activated NK cells produce IFN-g, which is required for the upregulation of TRAIL and the control of tumor growth [59]. Specifically, IFN-g plays a key role in primary and secondary immunity generated by NK cell sensitive tumors that express CD80 in vivo [60]. However, IFN-g can have paradoxical functions. Transient production of IFN-g by regulatory T cells might impinge IFN type II R1 and R2 bearing conventional T cells (inducing apoptosis) and stimulate production of indoleamine 2,3 dioxygenase and inducible nitric oxide synthase from APCs, as shown in organ transplantation and autoimmunity [61]. Whether such detrimental effects of type II IFN could be occurring during spontaneous tumor progression or antitumor vaccination remains unknown.

Killing two birds with one stone: IKDC The current paradigm for tumor-specific T-cell priming relies on a ‘two-step’ process: first, the tumor destruction that provides antigens and, second, the processing of these antigens by DCs. The cross-presentation of tumor-associated antigens is known to depend on the activation of DCs induced by apoptotic tumor cells, local inflammatory mediators and innate immune effectors, especially NK cells [62]. Recently, an alternative one-step process of Current Opinion in Immunology 2007, 19:224–231

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tumor immunosurveillance was unveiled owing to the discovery of a novel innate effector, called interferon producing killer dendritic cell (IKDC), which acts simultaneously as a killer and as a messenger [58,63]. DCs endowed with poorly characterized cytolytic functions have previously been documented in humans and rodents, although the precise nature of the DC subset responsible for cytolysis remained elusive. TRAIL- or FasL-mediated mechanisms were involved in the lysis of tumor cells by conventional DCs. Josien et al. [64] described a subset of splenic rat DC-expressing NKRP1 able to kill YAC-1, the most common NK cell target, in a Ca2+-dependent manner. More recently, Pillarisetty et al. [65] claimed the identification of a subset of cells that simultaneously mediated cytotoxicity and antigen presentation. However, the isolation of these cells based on the only NK1.1 and CD11c markers could not rule out a contamination with NK cells.

antitumor effects involving DCs and/or cognate effectors [66,67]. Our initial work highlighted that translocation of calreticulin at the plasma membrane of tumor cells prior to cell death induced by anthracyclins is a mandatory checkpoint for the immunoadjuvant effects of chemotherapy. Indeed, licensing of DC uptake depended upon calreticulin exposure or inhibition of the PP1/ GADD34 phosphatase in tumor cells [68]. C-Kit tyrosine kinase inhibitors can also promote NK cell activation through DCs [69] and memory T cell responses [70]. Finally, the efficacy of CpG against Listeria and possibly tumors involves cooperation between innate and cognate effectors. In mice, CpG stimulates host production of IL-12 and drives Th1-skewed immune responses [71]. Freshly isolated human NK cells induce IFN-a production by pDCs following CpG activation (both NK cells and pDCs that bear TLR9) and become highly cytotoxic.

Conclusions IKDCs, defined as CD11clowB220+CD49b/NK1.1+ cells, represent 0.5–1% of splenic CD11c+ cells. IKDCs can be detected in lymphoid organs and blood, as well as in lung, gut, liver and skin [63]. The IKDC is a multitasking cell that shares similarities with both NK cells and DCs. Like NK cells, IKDCs express inhibitory (Ly49 family members, NKG2A and KLRG1) and activating (NKG2D) receptors, and lyse a variety of tumor cell lines while secreting IFN-g. However, IKDCs but not NK cells upregulate MHC II and co-stimulatory molecules upon activation and tumor encounter ([58] and our unpublished data). The treatment of mice bearing B16F10 melanomas with the tyrosine kinase inhibitor imatinib mesylate (IM) plus IL-2 induces the activation and intratumoral recruitment of IKDCs. The potent tumoricidal effect of IKDCs is mediated through a developed killing machinery. Our recent findings indicate that IL-15 is a pivotal cytokine crucial for IKDC homeostasis, amplification and activation in vivo following IM + IL-2 (our unpublished data). Upon IL-15–IL-15Ra encounter, IKDCs acquire large amounts of perforin and granzyme B, and their killing activity is markedly enhanced and independent of NKG2D expression. Whether IKDC can phagocytose dead material and differentiate into activated APCs remains unclear. However, unlike NK cells, IKDCs express high levels of MHC II when present in the tumor bed. Listeria monocytogenes can activate IKDCs to become highly cytotoxic, to upregulate MHC II and costimulatory molecules, to migrate to the T-cell area of LN, and to effectively present antigen to local T cells [63].

Therapy-induced stimuli eliciting the innate/ cognate immune cooperation Apoptosis inducers might provide the immune system with tumor antigens and danger signals. For example, anthracyclins and gemcitabine have been shown to trigger Current Opinion in Immunology 2007, 19:224–231

Important links between innate and cognate immunity have been demonstrated in the setting of infectious insults rather than growing tumor burdens that rapidly subvert immune responses. For instance, the presence of TLR3 has been highlighted to be an important mechanism of solid organ immune privilege. Highly activated CD8+ T cells can coexist with hepatocytes that express the relevant autoantigen without causing overt autoimmune hepatitis. Triggering of TLR3 using Poly I:C (but not TLR9L) was required to break immune tolerance and to provoke organ destruction. DCand macrophage-derived IFN-a and TNF-a could induce CXCL9 secretion by hepatocytes and promote chemotaxis of CXCR3-expressing antigen-specific CD8+ T cells that promote hepatic failure. Therefore, in addition to raising specific T-cell responses, TLR triggering of APCs might provide the complementary signals for T-cell recruitment at the site of antigen [72]. Even in the setting of tumorinduced tolerance, antitumor immune responses can occur at the onset of tumor development, and long-term survival can occur following conventional cytototoxic therapy or immunotherapy. Unraveling the molecular mechanisms of cell death initiated by innate or cognate effectors and/or immunogenic cytotoxic agents could provide clues as to which DAMPs or endogenous danger signals are relevant against tumor progression.

References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as:  of special interest  of outstanding interest 1.

Fujii S, Liu K, Smith C, Bonito AJ, Steinman RM: The linkage of innate to adaptive immunity via maturing dendritic cells in vivo requires CD40 ligation in addition to antigen presentation and CD80/86 costimulation. J Exp Med 2004, 199:1607-1618. www.sciencedirect.com

Tumour innate and cognate immunity Ghiringhelli et al. 229

2. 

Sporri R, Reis e Sousa C: Inflammatory mediators are insufficient for full dendritic cell activation and promote expansion of CD4+ T cell populations lacking helper function. Nat Immunol 2005, 6:163-170. This article demonstrates that indirect activation by inflammatory mediators generated DCs that failed to induce direct T helper cell differentiation. In contrast, exposure to pathogen components resulted in fully activated DCs that promoted T helper responses. These results indicate that inflammation cannot substitute for contact with pathogen components in DC activation.

Zitvogel L: Dendritic cells directly trigger NK cell functions: cross-talk relevant in innate anti-tumor immune responses in vivo. Nat Med 1999, 5:405-411. 18. Terme M, Tomasello E, Maruyama K, Crepineau F, Chaput N, Flament C, Marolleau JP, Angevin E, Wagner EF, Salomon B et al.: IL-4 confers NK stimulatory capacity to murine dendritic cells: a signaling pathway involving KARAP/DAP12-triggering receptor expressed on myeloid cell 2 molecules. J Immunol 2004, 172:5957-5966.

3.

Janeway CA Jr: How the immune system works to protect the host from infection: a personal view. Proc Natl Acad Sci USA 2001, 98:7461-7468.

19. Martin-Fontecha A, Thomsen LL, Brett S, Gerard C, Lipp M, Lanzavecchia A, Sallusto F: Induced recruitment of NK cells to lymph nodes provides IFN-g for TH1 priming. Nat Immunol 2004, 5:1260-1265.

4.

Sotomayor EM, Borrello I, Rattis FM, Cuenca AG, Abrams J, Staveley-O’Carroll K, Levitsky HI: Cross-presentation of tumor antigens by bone marrow-derived antigen-presenting cells is the dominant mechanism in the induction of T-cell tolerance during B-cell lymphoma progression. Blood 2001, 98:1070-1077.

20. Smyth MJ, Teng MW, Swann J, Kyparissoudis K, Godfrey DI, Hayakawa Y: CD4+CD25+ T regulatory cells suppress NK cell-mediated immunotherapy of cancer. J Immunol 2006, 176:1582-1587.

5.

Vicari AP, Caux C, Trinchieri G: Tumour escape from immune surveillance through dendritic cell inactivation. Semin Cancer Biol 2002, 12:33-42.

6.

Almand B, Resser JR, Lindman B, Nadaf S, Clark JI, Kwon ED, Carbone DP, Gabrilovich DI: Clinical significance of defective dendritic cell differentiation in cancer. Clin Cancer Res 2000, 6:1755-1766.

7.

8.

9.

Wang T, Niu G, Kortylewski M, Burdelya L, Shain K, Zhang S, Bhattacharya R, Gabrilovich D, Heller R, Coppola D et al.: Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med 2004, 10:48-54. Cheng F, Wang HW, Cuenca A, Huang M, Ghansah T, Brayer J, Kerr WG, Takeda K, Akira S, Schoenberger SP et al.: A critical role for Stat3 signaling in immune tolerance. Immunity 2003, 19:425-436. Karre K, Ljunggren HG, Piontek G, Kiessling R: Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature 1986, 319:675-678.

10. Pende D, Rivera P, Marcenaro S, Chang CC, Biassoni R, Conte R, Kubin M, Cosman D, Ferrone S, Moretta L et al.: Major histocompatibility complex class I-related chain A and UL16-binding protein expression on tumor cell lines of different histotypes: analysis of tumor susceptibility to NKG2D-dependent natural killer cell cytotoxicity. Cancer Res 2002, 62:6178-6186. 11. Piccioli D, Sbrana S, Melandri E, Valiante NM: Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells. J Exp Med 2002, 195:335-341. 12. Vitale M, Della Chiesa M, Carlomagno S, Pende D, Arico M, Moretta L, Moretta A: NK-dependent DC maturation is mediated by TNFa and IFNg released upon engagement of the NKp30 triggering receptor. Blood 2005, 106:566-571. 13. Mailliard RB, Son YI, Redlinger R, Coates PT, Giermasz A, Morel PA, Storkus WJ, Kalinski P: Dendritic cells mediate NK cell help for Th1 and CTL responses: two-signal requirement for the induction of NK cell helper function. J Immunol 2003, 171:2366-2373. 14. Kelly JM, Darcy PK, Markby JL, Godfrey DI, Takeda K, Yagita H, Smyth MJ: Induction of tumor-specific T cell memory by NK cell-mediated tumor rejection. Nat Immunol 2002, 3:83-90. 15. Mocikat R, Braumuller H, Gumy A, Egeter O, Ziegler H, Reusch U, Bubeck A, Louis J, Mailhammer R, Riethmuller G et al.: Natural killer cells activated by MHC class I(low) targets prime dendritic cells to induce protective CD8 T cell responses. Immunity 2003, 19:561-569.

21. Ghiringhelli F, Menard C, Terme M, Flament C, Taieb J, Chaput N, Puig PE, Novault S, Escudier B, Vivier E et al.: CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner. J Exp Med 2005, 202:1075-1085. 22. Ebata K, Shimizu Y, Nakayama Y, Minemura M, Murakami J, Kato T, Yasumura S, Takahara T, Sugiyama T, Saito S: Immature NK cells suppress dendritic cell functions during the development of leukemia in a mouse model. J Immunol 2006, 176:4113-4124. 23. Granucci F, Zanoni I, Pavelka N, Van Dommelen SL, Andoniou CE, Belardelli F, Degli Esposti MA, Ricciardi-Castagnoli P: A contribution of mouse dendritic cell-derived IL-2 for NK cell activation. J Exp Med 2004, 200:287-295. 24. Borg C, Jalil A, Laderach D, Maruyama K, Wakasugi H, Charrier S, Ryffel B, Cambi A, Figdor C, Vainchenker W et al.: NK cell activation by dendritic cells (DCs) requires the formation of a synapse leading to IL-12 polarization in DCs. Blood 2004, 104:3267-3275. 25. Koka R, Burkett P, Chien M, Chai S, Boone DL, Ma A: Cutting edge: murine dendritic cells require IL-15Ra to prime NK cells. J Immunol 2004, 173:3594-3598. 26. Semino C, Angelini G, Poggi A, Rubartelli A: NK/iDC interaction results in IL-18 secretion by DCs at the synaptic cleft followed by NK cell activation and release of the DC maturation factor HMGB1. Blood 2005, 106:609-616. 27. Sivori S, Falco M, Della Chiesa M, Carlomagno S, Vitale M, Moretta L, Moretta A: CpG and double-stranded RNA trigger human NK cells by Toll-like receptors: induction of cytokine release and cytotoxicity against tumors and dendritic cells. Proc Natl Acad Sci USA 2004, 101:10116-10121. 28. Brigl M, Brenner MB: CD1: antigen presentation and T cell function. Annu Rev Immunol 2004, 22:817-890. 29. Wu DY, Segal NH, Sidobre S, Kronenberg M, Chapman PB: Cross-presentation of disialoganglioside GD3 to natural killer T cells. J Exp Med 2003, 198:173-181. 30. Hayday AC: gd cells: a right time and a right place for a conserved third way of protection. Annu Rev Immunol 2000, 18:975-1026. 31. Gober HJ, Kistowska M, Angman L, Jeno P, Mori L, De Libero G: Human T cell receptor gd cells recognize endogenous mevalonate metabolites in tumor cells. J Exp Med 2003, 197:163-168. 32. Fujii S, Shimizu K, Kronenberg M, Steinman RM: Prolonged IFN-g-producing NKT response induced with agalactosylceramide-loaded DCs. Nat Immunol 2002, 3:867-874.

16. Adam C, King S, Allgeier T, Braumuller H, Luking C, Mysliwietz J, Kriegeskorte A, Busch DH, Rocken M, Mocikat R: DC–NK cell cross talk as a novel CD4+ T-cell-independent pathway for antitumor CTL induction. Blood 2005, 106:338-344.

33. Leslie DS, Vincent MS, Spada FM, Das H, Sugita M, Morita CT, Brenner MB: CD1-mediated gd T cell maturation of dendritic cells. J Exp Med 2002, 196:1575-1584.

17. Fernandez NC, Lozier A, Flament C, Ricciardi-Castagnoli P, Bellet D, Suter M, Perricaudet M, Tursz T, Maraskovsky E,

34. Dinarello CA: Interleukin-1. Cytokine Growth Factor Rev 1997, 8:253-265.

www.sciencedirect.com

Current Opinion in Immunology 2007, 19:224–231

230 Tumour immunology

35. Di Virgilio F, Chiozzi P, Ferrari D, Falzoni S, Sanz JM, Morelli A, Torboli M, Bolognesi G, Baricordi OR: Nucleotide receptors: an emerging family of regulatory molecules in blood cells. Blood 2001, 97:587-600.

52. Maecker B, Mougiakakos D, Zimmermann M, Behrens M, Hollander S, Schrauder A, Schrappe M, Welte K, Klein C: Dendritic cell deficiencies in pediatric acute lymphoblastic leukemia patients. Leukemia 2006, 20:645-649.

36. la Sala A, Ferrari D, Corinti S, Cavani A, Di Virgilio F, Girolomoni G: Extracellular ATP induces a distorted maturation of dendritic cells and inhibits their capacity to initiate Th1 responses. J Immunol 2001, 166:1611-1617.

53. Faith A, Peek E, McDonald J, Urry Z, Richards DF, Tan C, Santis G, Hawrylowicz C: Plasmacytoid dendritic cells from human lung cancer draining lymph nodes induce Tc1 responses. Am J Respir Cell Mol Biol 2006, in press.

37. O’Connell J, Houston A, Bennett MW, O’Sullivan GC, Shanahan F: Immune privilege or inflammation? Insights into the Fas ligand enigma. Nat Med 2001, 7:271-274.

54. Salio M, Cella M, Vermi W, Facchetti F, Palmowski MJ, Smith CL, Shepherd D, Colonna M, Cerundolo V: Plasmacytoid dendritic cells prime IFN-g-secreting melanoma-specific CD8 lymphocytes and are found in primary melanoma lesions. Eur J Immunol 2003, 33:1052-1062.

38. Seino K, Kayagaki N, Okumura K, Yagita H: Antitumor effect of locally produced CD95 ligand. Nat Med 1997, 3:165-170. 39. Tvinnereim AR, Hamilton SE, Harty JT: Neutrophil involvement in cross-priming CD8+ T cell responses to bacterial antigens. J Immunol 2004, 173:1994-2002. 40. Rescigno M, Piguet V, Valzasina B, Lens S, Zubler R, French L, Kindler V, Tschopp J, Ricciardi-Castagnoli P: Fas engagement induces the maturation of dendritic cells (DCs), the release of interleukin (IL)-1b, and the production of interferon g in the absence of IL-12 during DC–T cell cognate interaction: a new role for Fas ligand in inflammatory responses. J Exp Med 2000, 192:1661-1668. 41. Shi Y, Evans JE, Rock KL: Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 2003, 425:516-521. 42. Scaffidi P, Misteli T, Bianchi ME: Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 2002, 418:191-195. 43. Park JS, Svetkauskaite D, He Q, Kim JY, Strassheim D, Ishizaka A, Abraham E: Involvement of Toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem 2004, 279:7370-7377. 44. Ito N, Demarco RA, Mailliard RB, Han J, Rabinowich H, Kalinski P, Stolz DB, Zeh HJ 3rd, Lotze MT: Cytolytic cells induce HMGB1 release from melanoma cell lines. J Leuco Biol 2006, 81:75-83. 45. Ohteki T, Suzue K, Maki C, Ota T, Koyasu S: Critical role of IL-15–IL-15R for antigen-presenting cell functions in the innate immune response. Nat Immunol 2001, 2:1138-1143. 46. Munger W, DeJoy SQ, Jeyaseelan R Sr, Torley LW, Grabstein KH, Eisenmann J, Paxton R, Cox T, Wick MM, Kerwar SS: Studies evaluating the antitumor activity and toxicity of interleukin-15, a new T cell growth factor: comparison with interleukin-2. Cell Immunol 1995, 165:289-293. 47. Waldmann TA, Dubois S, Tagaya Y: Contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes: implications for immunotherapy. Immunity 2001, 14:105-110. 48. Le Bon A, Tough DF: Links between innate and adaptive immunity via type I interferon. Curr Opin Immunol 2002, 14:432-436. 49. Dunn GP, Bruce AT, Sheehan KC, Shankaran V, Uppaluri R,  Bui JD, Diamond MS, Koebel CM, Arthur C, White JM et al.: A critical function for type I interferons in cancer immunoediting. Nat Immunol 2005, 6:722-729. This article demonstrates that type I IFNs are crucial for rejection of highly immunogenic syngeneic mouse sarcomas and in protecting the host from the formation of primary carcinogen-induced tumors. Tumors that form in IFN-type I receptor knock-out mice are more immunogenic than those that form in wild-type mice. 50. Treilleux I, Blay JY, Bendriss-Vermare N, Ray-Coquard I, Bachelot T, Guastalla JP, Bremond A, Goddard S, Pin JJ, Barthelemy-Dubois C et al.: Dendritic cell infiltration and prognosis of early stage breast cancer. Clin Cancer Res 2004, 10:7466-7474. 51. Tang TJ, Vukosavljevic D, Janssen HL, Binda RS, Mancham S, Tilanus HW, Ijzermans JN, Drexhage H, Kwekkeboom J: Aberrant composition of the dendritic cell population in hepatic lymph nodes of patients with hepatocellular carcinoma. Hum Pathol 2006, 37:332-338. Current Opinion in Immunology 2007, 19:224–231

55. Barchet W, Cella M, Colonna M: Plasmacytoid dendritic cells — virus experts of innate immunity. Semin Immunol 2005, 17:253-261. 56. Longman RS, Braun D, Pellegrini S, Rice C, Darnell R, Albert ML: Dendritic cell maturation alters intracellular signaling networks, enabling differential effects of IFNa/b on antigen cross-presentation. Blood 2007, 109(3):1113-1122. 57. Dunn GP, Koebel CM, Schreiber RD: Interferons, immunity and cancer immunoediting. Nat Rev Immunol 2006, 6:836-848. 58. Taieb J, Chaput N, Menard C, Apetoh L, Ullrich E, Bonmort M,  Pequignot M, Casares N, Terme M, Flament C et al.: A novel dendritic cell subset involved in tumor immunosurveillance. Nat Med 2006, 12:214-219. This article describes, for the first time, a new type of DC called IKDC that has both antigen-presentation function and killer capacity. 59. Takeda K, Hayakawa Y, Smyth MJ, Kayagaki N, Yamaguchi N, Kakuta S, Iwakura Y, Yagita H, Okumura K: Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nat Med 2001, 7:94-100. 60. Kelly JM, Takeda K, Darcy PK, Yagita H, Smyth MJ: A role for IFN-g in primary and secondary immunity generated by NK cell-sensitive tumor-expressing CD80 in vivo. J Immunol 2002, 168:4472-4479. 61. Wood KJ, Sawitzki B: Interferon g: a crucial role in the function of induced regulatory T cells in vivo. Trends Immunol 2006, 27:183-187. 62. Huang AY, Golumbek P, Ahmadzadeh M, Jaffee E, Pardoll D, Levitsky H: Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens. Science 1994, 264:961-965. 63. Chan CW, Crafton E, Fan HN, Flook J, Yoshimura K, Skarica M,  Brockstedt D, Dubensky TW, Stins MF, Lanier LL et al.: Interferonproducing killer dendritic cells provide a link between innate and adaptive immunity. Nat Med 2006, 12:207-213. See anotation to [58]. 64. Josien R, Heslan M, Soulillou JP, Cuturi MC: Rat spleen dendritic cells express natural killer cell receptor protein 1 (NKR-P1) and have cytotoxic activity to select targets via a Ca2+dependent mechanism. J Exp Med 1997, 186:467-472. 65. Pillarisetty VG, Katz SC, Bleier JI, Shah AB, Dematteo RP: Natural killer dendritic cells have both antigen presenting and lytic function and in response to CpG produce IFN-g via autocrine IL-12. J Immunol 2005, 174:2612-2618. 66. Casares N, Pequignot MO, Tesniere A, Ghiringhelli F, Roux S, Chaput N, Schmitt E, Hamai A, Hervas-Stubbs S, Obeid M et al.: Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med 2005, 202:1691-1701. 67. Lake RA, Robinson BW: Immunotherapy and chemotherapy — a practical partnership. Nat Rev Cancer 2005, 5:397-405. 68. Obeid M, Tesniere M, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL, Castedo M, Mignot G, Panaretakis T, Casares N et al.: Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med 2007, 13:54-61. 69. Borg C, Terme M, Taieb J, Menard C, Flament C, Robert C, Maruyama K, Wakasugi H, Angevin E, Thielemans K et al.: www.sciencedirect.com

Tumour innate and cognate immunity Ghiringhelli et al. 231

Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects. J Clin Invest 2004, 114:379-388. 70. Wang H, Cheng F, Cuenca A, Horna P, Zheng Z, Bhalla K, Sotomayor EM: Imatinib mesylate (STI-571) enhances antigenpresenting cell function and overcomes tumor-induced CD4+ T-cell tolerance. Blood 2005, 105:1135-1143.

71. Klinman DM: Immunotherapeutic uses of CpG oligodeoxynucleotides. Nat Rev Immunol 2004, 4:249-258. 72. Lang KS, Georgiev P, Recher M, Navarini AA, Bergthaler A, Harris NL, Junt T, Odermatt B, Clavien PA, Pircher H et al.: Immunoprivileged status of the liver is controlled by Toll-like receptor signaling. J Clin Invest 2006, 116:2456-2463.

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