Role of Chemokines and Chemokine Receptors in Shaping the Effector Phase of the Antitumor Immune Response

Published OnlineFirst December 7, 2012; DOI: 10.1158/0008-5472.CAN-12-2027

Cancer Review Research

Katarzyna Franciszkiewicz1, Alexandre Boissonnas2, Marie Boutet1, Christophe Combadiere 2, and Fathia Mami-Chouaib1

Abstract Immune system–mediated eradication of neoplastic cells requires induction of a strong long-lasting antitumor T-cell response. However, generation of tumor-specific effector T cells does not necessarily result in tumor clearance. CTL must firstbeabletomigratetothetumorsite,infiltrate the tumor tissue, and interact with the target to finally trigger effector functions indispensable for tumor destruction. Chemokines are involved in circulation, homing, retention, and activation of immunocompetent cells. Although some of them are known to contribute to tumor growth and metastasis, others are responsible for changes in the tumor microenvironment that lead to extensive infiltration of lymphocytes, resulting in tumor eradication. Given their chemoattractive and activating properties, a role for chemokines in the development of the effector phase of the antitumor immune response has been suggested. Here, we emphasize the role of the chemokine–chemokine receptor network at multiple levels of the T-cell–mediated antitumor immune response. The identification of chemokine-dependent molecular mechanisms implicated in tumor-specific CTL trafficking, retention, and regulation of their in situ effector functions may offer new perspectives for development of innovative immunotherapeutic approaches to cancer treatment. Cancer Res; 72(24); 1–8. 2012 AACR.

Introduction critical step in optimization of current cancer immunotherapy The identification of tumor-associated antigens (TAA) and protocols. the isolation of tumor-specific cytotoxic T cells have led to Chemokines coordinate circulation, homing, and retention great efforts in developing immunotherapeutic approaches to of immune cells. Originally characterized for their ability to overcoming tumor invasion. Immunotherapy represents a induce leukocyte chemoattraction, they are now recognized to fl promising approach to cancer treatment, with less severe side orchestrate a wide array of leukocyte functions during in am- effects than conventional strategies. Major strategies have mation and immunity (2). Indeed, in addition to their chemo- focused on the induction of T-cell–mediated antitumor tactic properties, chemokines can directly regulate T-cell responses. However, the generation of antigen-specific development, priming, and effector functions (3). In the con- tumor-reactive T cells has rarely been translated into thera- text of cancer immunosurveillance, chemokines orchestrate peutic success. One of the reasons for the failure of the immune the spatiotemporal distribution of immunocompetent cells system to eradicate cancer cells is a defect in T-cell migration crucial for induction of antitumor immune response and to the tumor site (1). To destroy established tumors, CTL must optimal effector function (4, 5). Chemokines constitute a large traffic to and infiltrate the tumor tissue before specific acti- family of small, mostly secreted proteins comprising more than vation and triggering of target cell death. The dissection of 50 members, which interact with 20 chemokine receptors. – cellular and molecular processes that enhance T-cell recruit- Chemokine receptors are G-protein coupled 7-transmem- – ment and ultimately lead to tumor elimination is therefore a brane domain receptors responsible not only for triggering intracellular signals resulting in cell polarization, migration, and adhesion, but also for contributing to gene expression, cell proliferation, and survival (2). Most chemokines bind to more Authors' Affiliations: 1Institut National de la Sante et de la Recherche Medicale (INSERM) U753, Team 1: Tumor Antigens and T-cell Reactivity, than 1 receptor. On the other hand, chemokine receptors Integrated Research Cancer Institute in Villejuif (IRCIV), Institut de display overlapping ligand specificities with variable affinity Cancerologie Gustave Roussy (IGR), Villejuif; and 2INSERM UMR-S 945 and functional activities (3). and Universite Pierre et Marie Curie (UPMC University Paris 06), Laboratory – of Immunity and Infection, Boulevard de l'Hopital,^ Paris, France There is now overwhelming evidence that the chemokine chemokine receptor system is directly or indirectly involved in Corresponding Author: Fathia Mami-Chouaib, Institut National de la Sante et de la Recherche Medicale (INSERM) U753, IGR, 39 rue tumor development (6). On the basis of their role in cell Camille-Desmoulins, F-94805 Villejuif, France. Phone: 33-1-42-11-49- migration, chemokines contribute to tumor dissemination 65; Fax: 33-1-42-11-52-88; E-mail: [email protected] and metastasis. Moreover, chemokine-triggered signaling doi: 10.1158/0008-5472.CAN-12-2027 pathways can facilitate tumor cell proliferation and contribute 2012 American Association for Cancer Research. to neovascularization. Tumor-derived chemokines are also

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responsible for shaping the tumor microenvironment into an provide CD4 T-cell help for CD8 T-cell priming, where 2 immunosuppressive site, determining the qualitative and lymphocyte types have to encounter the same APC (13). It has quantitative composition of tumor-infiltrating immune cells been shown that CCL19 secreted by mature dendritic cells and affecting their maturation and activation status (7). In increases na€ve CD4 T-cell scanning behavior and their consequence, tumors seem to use chemokines to evade immu- response to rare cognate antigens (14). Moreover, engagement nosurveillance and actively progress. Nevertheless, expression of na€ve CD4 T cells with APC triggers secretion of CCL3 and of some chemokines within the tumor bed has been associated CCL4, which favor CCR5-dependent guidance of na€ve CD8 T with an effective antitumor immune response, an angiostatic cells toward dendritic cells (DC)-CD4 T-cell conjugates (15). effect, a low recurrence rate and increased patient survival. Interestingly, CCR5-dependent recruitment of CD8 T cells to Indeed, some chemokines are responsible for changes in dendritic cells engaging TAA-specific T cells increases the chemoattractive properties of the tumor microenvironment efficiency of alternative TAA-specificna€ve CD8 T-cell priming that allow extensive infiltration of leukocytes (7). Thus, che- (16). mokines and chemokine receptors represent valuable targets Following the antigen encounter and T-cell expansion, a for optimizing antitumor immune responses. In this context, modification in the general chemokine receptor expression the major concern of tumor immunologists is to better under- profile is required to enable appropriate redistribution of stand chemokine-mediated pathways involved in T-cell activated T cells. This modification consists of downregulation recruitment at the tumor site and in regulating their intratu- of receptors that mediate entry and the encounter with APC in moral effector functions. In this review, we present findings the lymph node, and of upregulation of other receptors to first implicating chemokines in regulation of the CTL-mediated egress from the lymph node and then sensitize T cells to effector phase of the antitumor immune response and we infiltrate the tumor site. Pertussis toxin has been shown to provide insights into their therapeutic applications. affect lymphocyte egress from the lymph node, suggesting an – implication of chemokine receptors. Indeed, one of the initial Role of Chemokines in Priming the T-Cell events in effector T-cell differentiation is downregulation of Mediated Immune Response CCR7 and upregulation of receptors specific to chemokines Development of an effective antitumor immune response expressed in target tissues, such as CCR1, CCR2, CCR3, CCR5, relies on the coordinated interactions of immunocompetent and CXCR3 (17). Acquisition of an appropriate migration cells, the spatiotemporal distribution of which is in part program is thus crucial for targeting the right cell to the right orchestrated by chemokines (Fig. 1). Acting through their place. cognate receptors, chemokines regulate trafficking between the tumor site and lymph nodes. To become competent killer Regulation of T-Cell Recruitment at the Tumor cells, CTL require efficient priming by professional antigen- Site by Chemokines presenting cells (APC) and cognate licensing of dendritic cells To exert their functions, recently primed T cells leave the þ þ by CD4 T cells (8). For this purpose, na€ve CD8 T cells lymph node and migrate to the tumor site, in which they continuously traffic through secondary lymphoid organs in physically engage cognate T-cell receptor (TCR) ligand-expres- which they systematically scan the surface of dendritic cells sing targets. Chemokines play a major role in the recruitment searching for TAA. Na€ve T cells express CCR7, which recog- of effector T cells within the tumor microenvironment. Anti- nizes constitutively expressed CCL19 and CCL21. CCL21, pro- tumor CTL respond to numerous inflammatory chemokines, duced by lymph nodes, Peyer's patch–associated high endo- mainly CCL3 (18), CCL5 (19), CCL20 (20), and CXCL10 (21), thelial venules, and afferent lymphatic vessels, triggers a mul- which can be produced at the tumor site (22). Therefore, the tistep process for recruitment of na€ve lymphocytes (9). Sim- intratumoral production of chemokines, which determine ilarly, CCL21-CCR7 signaling is involved in trafficking of optimal T-cell recruitment, is one of the key factors in an antigen-presenting dendritic cells. Indeed, their maturation efficient antitumor immune response. In this context, CCL5 into potent APC implies downregulation of tissue-specific was one of the first chemokines implicated in regulating chemokine receptors, such as CCR1, CCR5, and CCR6, and antitumor immunity (19). A role for CCR5 in T-cell recruitment upregulation of CCR7, which guides dendritic cells from sites of to the tumor site has been documented and local production of antigen exposure to the local lymph nodes via draining afferent CCL5 or CCL3 induces selective recruitment of CD8 T cells and lymphatic vessels (10). The pivotal role of CCR7 in these CTL-dependent tumor suppression in mouse models (23). processes was shown in CCR7-deficient mice, which displayed CCR5 ligands are detected in many human tumors, including reduced numbers of na€ve T cells in secondary lymphoid non–small-cell lung carcinoma (NSCLC), and can induce T-cell organs (11). Once in the lymph nodes, T cells display high infiltration. However, the role of CCL5 in the antitumor basal motility, enabling them to scan up to several thousand immune response remains controversial. In NSCLC, the pro- APC per hour. These steady-state movements are dependent duction of CCL5 has been associated with an active lympho- a on G i-coupled chemokine receptor signaling triggered by cyte-mediated response and represents a positive predictive CCL19 and CCL21 present in the lymph node T-cell zone (12). factor for patient survival (24). In contrast, high levels of CCL5 The major biologic relevance of na€ve T-cell motility within have been reported to correlate with poor prognosis in breast lymph nodes is to ensure recognition of a few antigen-bearing and cervical carcinomas (25). Although the cellular infiltrates dendritic cells by rare specific T cells. However, random were not investigated in these studies, it is conceivable that migration of T cells does not seem to be efficient enough to disease progression was related to tumor escape mechanisms

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Lymph node

CD4؉ CCR7 CD4 T cell Migration to MHC-II-TCR LN Maturation CD40–CD40L CCL19, 21 DC IL-2, IFNγ… Ag presentation IDC MHC-I-TCR CD8

؉ CD80/86-CD28 CD8 T cell CCR1, 5, 6, 9 CXCR4 Ag uptake Innate immunity Adaptive CCR2, 5 immunity CXCR3 CCR2, 5, 9 CXC3R1 M␾ CCR1, 2, 4, 5, 7, 8 ؉ NK CD8 CTL CD4؉ Th1 cell Danger signals CXCR1, 2, 3, 4 (HSP, Calreticulin…) CCR5 XCR1 CXCR3 NKT CCL2, 3, 5, 16 Lysis Dying tumor Migration to CXCL8, 9, 10, 12, 21 cells CCR5, 6 CCL3, 4, 5 the tumor CXCR3, 4, 6 CCL4 XCL1 CCL3 IFNα CXCL9, 10, 11 CXCL10, 12, 16 DC Specific lysis precursor PRR PAMP Treg CCR3, 4, 8

؉ CCR2, 4, 5, 6, 8 CD4 Th2 cell

CCR2, 4, 5, 6, 8 MDSC Tumor site

Figure 1. Chemokine network in the antitumor immune response. Malignant cells express pathogen-associated molecular patterns (PAMP) that can be recognized by pattern recognition receptors (PRR) on dendritic cells (DC) and macrophages (M), triggering release of chemokines. This results in recruitment and activation of M, NK, and NKT cells, which are able to lyse tumor cells. DC phagocytose apoptotic tumor cells and HSP-complexed tumor-derived peptides. Upon maturation, DC change their homing proprieties by downregulating tissue-speciﬁc chemokine receptors and upregulating CCR7 that guides them to CCL19/CCL21-rich lymph nodes (LN), where they present processed tumor þ þ peptides to CD4 and CD8 T cells. Activated T cells upregulate expression of chemokine receptors including CCR5 and CXCR3, and in response to intratumoral chemokines, circulating CTL inﬁltrate the tumor to destroy malignant cells. Tumor-derived chemokines are also responsible for recruitment of Treg cells and MDSC, which participate in establishment of a protumoral microenvironment. Ag, antigen; IDC, immature DC.

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through concurrent recruitment of immunosuppressive cell Interestingly, nonspecific tumor T cells can deeply infiltrate populations, such as tumor-associated macrophages and tumor tissues only upon tumor destruction by antigen-specific regulatory T (Treg) cells, or triggering of tumor-infiltrating CTL (35). This suggests that changes in the tumor microen- lymphocyte (TIL) apoptosis (26). Conversely, other groups vironment, such as secretion of chemokines induced by provided evidence for CCL3 and CCL5-induced T-cell prolif- destruction in tumor architecture, determine deep lymphocyte eration and activation (27, 28). infiltration. Therefore, delivery of appropriate chemokines into Among other chemokines implicated in tumor infiltration the tumor, reminiscent of what takes place during an effective by immune cells, CX3CL1 and CXCL16 have been associated T-cell response, would induce extensive infiltration of effector þ þ with high numbers of CD8 and CD4 TIL and with good cells, and thereby tumor destruction. prognosis in colorectal cancer (29). CCL20 has been detected in The contribution of chemokine receptors in T-cell retention breast cancer, in which it may be responsible for recruitment of at the tumor site is not well documented. We recently reported þ CCR6 memory T-cell subsets (30). The main chemokines that recruitment of CCR5 at the immune synapse formed attracting effector cells seem to be the CXCR3 ligands CXCL9 between TIL and tumor cells, resulted in inhibition of T-cell and CXCL10. In addition to their angiostatic activity, these responsiveness to a CCL5 chemotactic gradient. This CCR5 chemokines participate in the antitumor immune response clustering is dependent on the interaction of the aE(CD103)b7 through recruitment of T and natural killer (NK) cells (23). In integrin on T cells with its ligand, E-cadherin, on NSCLC cells renal cell carcinoma, intratumoral expression of CXCL9 and (36). An alternative mechanism of CTL retention in epithelial þ CXCL10 coincided with a high degree of CD8 T-cell infiltration tumors could implicate CCR6. CCR6 T cells were found to be and elicited an inverse correlation with tumor growth and more frequent in CD8 subpopulations isolated from TIL than recurrence after curative surgery (31). High levels of CXCL9 from PBL (36). This observation, together with efficient homing have also been associated with strong infiltration of malignant of CCR6 CTL to the tumor site, suggests that CCR6 is not melanoma by CD8 T cells and improvement in patient survival involved in T-cell recruitment to NSCLC but may play a local (32). Thus, it seems evident that chemokines contribute to the role. Apart from its function in cell trafficking, CCR6 was establishment of the immune response by orchestrating reported to be crucial for cell activation and conformational the distribution of its key cellular components and delivering changes in integrins (37). Furthermore, it has been shown that the generated effectors to the tumor site. Whether intratu- the interaction of CCR6 with its unique ligand, CCL20, is a moral chemokines promote immune surveillance or tumor critical event in the arrest of effector/memory T cells on escape depends on the composition of cell infiltrates, which endothelial cells (38). It is therefore conceivable that intratu- shape the environmental context through an immunoediting moral induction of CCR6, together with CD103, play a role in T- process. cell retention at the tumor site. Intratumoral T-Cell Location, Motility, and Costimulatory Role of Chemokines–Chemokine Retention Receptors in T-Cell Activation Positioning of CTL within tumor tissues is critical for an Although there is a considerable evidence implicating che- efficient antitumor immune response. After extravasation, mokines in antigen-experienced T-cell recruitment to the CTL must migrate through the interstitial space of the tumor site, their role in T-cell effector function is begging for tumor to recognize and kill target cells. Thus far, little is intensified investigation. It has been widely reported that known about the intratumoral migration of infiltrating CTL. engagement of chemokine receptors triggers a "go" signal that In experimental studies, CD8 T cells were mostly observed at competes with TCR-mediated "stop" signals, and thus nega- the tumor periphery, with limited infiltration into the tumor tively influences the stability and duration of the immune mass. A similar pattern was identified in human tissue synapse (39). Indeed, the gradient of some chemokines, includ- sections from metastatic melanoma. In NSCLC, T cells ing CXCL10 and CCL19 or CCL21, renders T cells ignorant of accumulate in stromal regions in which chemokines likely agonist peptide-MHC (pMHC), thus suppressing their activa- participate in controlling their motility and their entry into tion. However, CCL19 secreted by antigen-activated dendritic tumor islets (33). cells induces T-cell polarization and motility, resulting in Before establishing stable contact with target cells, TIL improved scanning of APC, thus increasing cognate pMHC migrate randomly within the tumor microenvironment, argu- encounters (14). ing against the early concept of T-cell guidance by a long-range Chemokines such as CXCL12 were also reported to enhance chemokine gradient. Two-photon microscopy studies provid- adhesion of T cells to dendritic cells by regulating the avidity/ ed insight into the dynamics of infiltration and elimination of affinity of key integrins, including leukocyte function-asso- solid tumors by immune cells (34, 35). After diapedesis, effector ciated antigen (LFA)-1 (37). Other chemokines, namely CCR7 T cells initially display random migration and start engaging a ligands bound on dendritic cells surface, may promote T-cell transient antigen-independent interaction with target cells. activation by improving immune synapse formation (40). CCR5 CTL that encounter antigen-expressing tumor cells, arrest and CXCR4 can be recruited to the immune synapse during T- their migration to establish a stable contact with the target. cell stimulation by APC, leading to a reduction in T-cell This leads to release of cytokines and cytotoxic granules sensitivity to other chemokine sources and enhanced T-cell resulting in tumor cell death. Once cancer cells are cleared, responses (27). It has also been proposed that APC-derived CTL resume motility to further search for new target cells. chemokines can act as costimulatory molecules for engaged T

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Table 1. Experimental and clinical trials based on intratumoral delivery of human chemokines Published OnlineFirstDecember7,2012;DOI:10.1158/0008-5472.CAN-12-2027 Human chemokines Mouse (M) or Human (H) (therapeutic approach) tumor model Inﬁltrating cells Immune response Treatment outcome References

cancerres.aacrjournals.org CCL2, CCL3 (rCCL2 Prostate cancer (M), breast Immune effector cells Increase of immune cell Tumor regression (5) and/or rCCL3) cancer (M), melanoma (M) infiltration into tumors CCL5 (rCCL5, Ad-RANTES-E1A) Mammary carcinoma (M) Macrophage, T cells T-cell proliferation, cytokine Tumor regression (27) T cells Lung cancer (M) secretion (52) CCL16 (rCCL16, CCL16 fusion Mammary carcinoma (M) Macrophage APC maturation and T-cell Tumor rejection (52) protein: LEC-chTNT3) priming Increase of tumor infiltration Tumor regression by immune cells CCL19 (rCCL19) Breast carcinoma (M) CD4, NK cells Unknown Tumor rejection (5) Cancer Research. þ CCL20 (rCCL20) Colon adenocarcinoma (M) CD8 T cells, DC Lymphocyte-dependent Tumor growth inhibition (5) on September 28, 2021. © 2012American Association for response CCL21 (rCCL21, nanoparticles, Melanoma (M and H T cells DC Lymphocyte-dependent Complete tumor (52) Ad-CCL21–transduced DC) phase I trial) response eradication Lung cancer (M) þ CCL22 (Ad-CCL22) Colon carcinoma (M) CD8 T cells, NK cells Tumor-infiltrating T cells Tumor growth inhibition (23) Melanoma (M) þ þ XCL1 (Ad-XCL1 þ IL-2 or Breast cancer (M) CD4 and CD8 T cells, Increase of tumor infiltration Tumor regression (46) þ þ IL-12 or XCL1 þ gp100- Melanoma (M) NK cells by CD4 and CD8 T (47) Response Immune Antitumor the and Chemokines pulsed DC) Neuroblastoma (H) cells, and neutrophils (53) (54) CXCL8 (rCXCL8) Ovarian carcinoma (M) Macrophages, neutrophils Unknown Tumor regression (5) acrRs 22)Dcme 5 2012 15, December 72(24) Res; Cancer CX3CL1 (rCX3CL1) Colorectal carcinoma (M) T cells, NK cells Increase of immune cell Tumor regression (29) infiltration into tumors CXCR1 (adoptive Melanoma (H) TIL Lymphocyte-dependent Increase of TIL recruitment (55) immunotherapy) response into CXCL1 and CXCL8- expressing tumors

NOTE: Respective human chemokines, DC, or adenoviral vectors encoding human chemokines were injected directly at the tumor site. Abbreviations: Ad, adenovirus; DC, dendritic cells; (H), human; (M), mouse; r: recombinant. OF5 Published OnlineFirst December 7, 2012; DOI: 10.1158/0008-5472.CAN-12-2027

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cells through chemokine receptors relocalized at the immune (45). Combination of chemokines with cytokines for cancer synapse (27). immunotherapy seems to deserve consideration. A combination of XCL1 and interleukin (IL)-2 has been reported to Role of Chemokines in Shaping the Tumor provide enhanced and long-term antitumor immunity (46). Microenvironment Other approaches to chemokine-based tumor immunother- The tumor microenvironment is characterized by chronic apy include vaccination strategies with TAA. Despite a great inflammation with the presence of cytokines and chemokines, deal of effort, the rate of objective cancer regression in vac- the profile of which dictates neoplastic outcome (7). Indeed, cinated patients has remained weak. Among the limitations of chemokines mediate accumulation of immunocompetent cells such vaccines are the insufficient numbers of recruited effector and participate in shaping a tumor-promoting or -suppressive cells and their inappropriate activation in an immunosuppres- microenvironment. CCR5 and CXCR3 predominate on Th1 sive tumor microenvironment (1). In this context, manipulat- cells, whereas Th2 cells preferentially express CCR3, CCR4, and ing the chemokine network may represent an attractive adju- CCR8. At the tumor site, Th1 cells colocalize with macrophages vant strategy (Table 1). A vaccine based on XCL1- and IL-2– and neutrophils, enhancing the cell-mediated immune secreting neuroblastoma cells induced an increase in T-cell response. In contrast, Th2-type inflammation is considered infiltration and resulted in complete or partial tumor remis- to be protumoral and is associated with a poor prognosis (41). sion in vaccinated patients (47). Adoptive immunotherapy is Chemokine receptor patterns that guide CD8 T cells to currently one of the most promising approaches, with signif- target tissues have not been studied as extensively as CD4 T icant positive results in preclinical and clinical trials (48, 49). cells but seem to be similar. Upon antigen-reencounter, CD8 T The success of adoptive therapy depends on the optimal cells secrete inflammatory chemokines, such as CCL3 and selection and/or genetic engineering of antigen-specific cells, CCL5, which increase infiltration of neutrophils, monocytes, induction of their proliferation while preserving effector func- and Th1 lymphocytes, and thus contribute to so-called auto- tions, engraftment ability, and efficient homing to the tumor recruitment of CTL, resulting in amplification of effector (50, 51). Because recruitment of transfused lymphocytes at the responses. However, the protective activity of TIL is often tumor site is one of the critical steps, intratumoral expression compromised by immunosuppressive tumor microenviron- of adequate chemokines represents one of the strategies for ment components, including Treg cells. Treg can be actively improving adoptive immunotherapy. Moreover, redirecting attracted to the tumor mostly via CCR4. Infiltration by Treg of the migratory properties of adoptively transferred T cells ovarian tumors producing high levels of CCL17 and CCL22 toward chemokine-secreting tumors can be achieved by genet- correlated with unfavorable prognosis (42). Treg cells, ic expression of appropriate chemokine receptors. Thus, the recruited through CCL22-CCR4, can be activated in lymphoid intratumoral production of chemokines, which determine the infiltrates surrounding breast tumors, leading to an adverse optimal CTL recruitment, is one of the key factors for efficient clinical outcome (43). Other immunosuppressive cells partic- antitumor responses. Any alteration can result in tumor eva- ipating in shaping the tumor microenvironment are myeloid- sion and represent one of the conceivable reasons for the derived suppressor cells (MDSC; Fig. 1). Once recruited within failure of adoptive transfer or vaccination-based immu- tumors in a CCR2, CXCR4, or CXCR2-dependent manner, notherapies (4). MDSC have a significant effect on tumor progression, mainly through suppression of antitumor effectors (44). Thus, by Concluding Remarks determining the composition of cellular infiltrates, intratu- The success of cancer immunotherapeutic strategies moral chemokines continuously shape the tumor microenvi- relies on the generation of efficacious effector mechanisms ronment and regulate the extent of antitumor immune associated with the presence of high-avidity tumor-specific responses. CTL. Chemokines contribute to induction of an effective immune response, orchestrating distribution of its key cel- Chemokines in Cancer Immunotherapy lular components, and delivering the generated effectors to Strategies of chemokine–chemokine receptor–based tumor the target. It should, however, be noted that the chemokine– immunotherapy are aimed at eradicating tumors by inhibiting chemokine receptor network is also implicated in immune survival and metastasis of malignant cells. The overexpression system homeostasis, thus limiting its manipulation in a of chemokines at the tumor site usually resulted in infiltration clinical setting. Despite these obstacles, intensified investi- by host leukocytes; however, disease outcome was more diver- gation of the role of chemokines in tumor immunosurveil- gent and related to the nature of the injected chemokines, the lance and immunosuppression may provide a gateway to subset of recruited immune cells and the tumor model (Table development of innovative and effective strategies for cancer 1). In mice, intratumoral delivery of chemokines can induce immunotherapy. tumor suppression and immunity to subsequent tumor chal- lenge through recruitment of dendritic cells, NK, and T cells (5). Disclosure of Potential Conflicts of Interest However, the efficacy of such approaches seems limited in No potential conflicts of interest were disclosed. humans (23). As chemokines are also responsible for attraction of immunosuppressive cells, such as Treg cells, blocking the Authors' Contributions Conception and design: K. Franciszkiewicz, M. Boutet, C. Combadiere, F. activity of the host CCR5 has been proposed for improving the Mami-Chouaib potency of dendritic cell–based vaccines against melanoma Development of methodology: F. Mami-Chouaib

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Acquisition of data (provided animals, acquired and managed patients, Grant Support provided facilities, etc.): F. Mami-Chouaib This work was supported by grants from Institut National de la Santeetdela Analysis and interpretation of data (e.g., statistical analysis, biostatistics, Recherche Medicale (INSERM), the Association pour la Recherche sur le Cancer computational analysis): F. Mami-Chouaib (ARC), the Ligue contre le Cancer, and Institut National du Cancer. K. Fran- Writing, review, and/or revision of the manuscript: K. Franciszkiewicz, A. ciszkiewicz was supported by a fellowship from the ARC and INCa. Boissonnas, M. Boutet, C. Combadiere, F. Mami-Chouaib Administrative, technical, or material support (i.e., reporting or orga- nizing data, constructing databases): K. Franciszkiewicz, F. Mami-Chouaib Received May 21, 2012; revised September 13, 2012; accepted October 1, 2012; Study supervision: F. Mami-Chouaib published OnlineFirst December 7, 2012.

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OF8 Cancer Res; 72(24) December 15, 2012 Cancer Research

Role of Chemokines and Chemokine Receptors in Shaping the Effector Phase of the Antitumor Immune Response

Katarzyna Franciszkiewicz, Alexandre Boissonnas, Marie Boutet, et al.

Cancer Res Published OnlineFirst December 7, 2012.

Updated version Access the most recent version of this article at: doi:10.1158/0008-5472.CAN-12-2027

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