Cancer-associated inflammation mobilizes a variety of leukocyte populations that can inhibit or enhance tumor cell growth in situ. These subsets include γδ T cells, which can infiltrate tumors and typically provide large amounts of antitumor cytokines, such as IFN-γ. By contrast, we report here that in a well-established transplantable (ID8 cell line) model of peritoneal/ovarian cancer, γδ T cells promote tumor cell growth. γδ T cells accumulated in the peritoneal cavity in response to tumor challenge and could be visualized within solid tumor foci. Functional characterization of tumor-associated γδ T cells revealed preferential production of interleukin-17A (IL-17), rather than IFN-γ. Consistent with this finding, both T cell receptor (TCR)δ-deficient and IL-17-deficient mice displayed reduced ID8 tumor growth compared with wild-type animals. IL-17 production by γδ T cells in the tumor environment was essentially restricted to a highly proliferative CD27 (−) subset that expressed Vγ6 instead of the more common Vγ1 and Vγ4 TCR chains. The preferential expansion of IL-17-secreting CD27 (−) Vγ6 (+) γδ T cells associated with the selective mobilization of unconventional small peritoneal macrophages (SPMs) that, in comparison with large peritoneal macrophages, were enriched for IL-17 receptor A, and for protumor and proangiogenic molecular mediators, which were upregulated by IL-17. Importantly, SPMs were uniquely and directly capable of promoting ovarian cancer cell proliferation. Collectively, this work identifies an IL-17-dependent lymphoid/myeloid crosstalk involving γδ T cells and SPMs that promotes tumor cell growth and thus counteracts cancer immunosurveillance. gamma-delta T cells | tumor immunologyD eveloping tumors are infiltrated by a variety of leukocyte subsets that can either promote or inhibit inflammation, and thus impact on cancer progression (1). Among such populations are γδ T cells, which are major players in lymphoid stress surveillance likely due to their recognition of stress-inducible molecules independently of MHC-mediated antigen presentation (2). Moreover, abundant IFN-γ secretion and cytotoxic effector functions endow γδ T cells with potent antitumor activity. This has been clearly documented in murine models of spontaneous (3), chemically induced (4), transgenic (5), and transplantable (6, 7) tumors. For example, in the widely used B16 melanoma model, γδ T cells were shown to infiltrate tumors very early and provided a critical source of IFN-γ that significantly delayed tumor growth (6, 7).Human γδ T cells also possess IFN-γ-secreting potential, which is displayed immediately at birth (8) and display cytotoxicity against tumor lines of diverse origin, including epithelial (9, 10) and hematological (11,12) tumors. This has prompted the development of cancer clinical trials targeting γδ T cells, which have produced encouraging, albeit highly variable, degrees of therapeutic responses (13-15). There is therefore great interest in maximizing the antitumor functions of γδ T cells for cancer ...

Tumor-infiltrating lymphocytes (TILs) are important prognostic factors in cancer progression and key players in cancer immunotherapy. Although γδ T lymphocytes can target a diversity of tumor cell types, their clinical manipulation is hampered by our limited knowledge of the molecular cues that determine γδ T cell migration toward tumors in vivo. In this study we set out to identify the chemotactic signals that orchestrate tumor infiltration by γδ T cells. We have used the preclinical transplantable B16 melanoma model to profile chemokines in tumor lesions and assess their impact on γδ TIL recruitment in vivo. We show that the inflammatory chemokine CCL2 and its receptor CCR2 are necessary for the accumulation of γδ TILs in B16 lesions, where they produce IFN-γ and display potent cytotoxic functions. Moreover, CCL2 directed γδ T cell migration in vitro toward tumor extracts, which was abrogated by anti-CCL2 neutralizing Abs. Strikingly, the lack of γδ TILs in TCRδ-deficient but also in CCR2-deficient mice enhanced tumor growth in vivo, thus revealing an unanticipated protective role for CCR2/CCL2 through the recruitment of γδ T cells. Importantly, we demonstrate that human Vδ1 T cells, but not their Vδ2 counterparts, express CCR2 and migrate to CCL2, whose expression is strongly deregulated in multiple human tumors of diverse origin, such as lung, prostate, liver, or breast cancer. This work identifies a novel protective role for CCL2/CCR2 in the tumor microenvironment, while opening new perspectives for modulation of human Vδ1 T cells in cancer immunotherapy.

Two distinct subsets of γδ T cells that produce interleukin 17 (IL-17) (CD27 − γδ T cells) or interferon-γ (IFN-γ) (CD27 + γδ T cells) develop in the mouse thymus, but the molecular determinants of their functional potential in the periphery remain unknown. Here we conducted a genome-wide characterization of the methylation patterns of histone H3, along with analysis of mRNA encoding transcription factors, to identify the regulatory frames of peripheral IFN-γ-producing or IL-17-producing γδ T cell subsets in vivo. We found that CD27 + γδ T cells were committed to the expression of Ifng but not Il17, whereas CD27 − γδ T cells displayed permissive chromatin configurations at loci related to both the T H 17 and T H 1 subsets of helper T cells and differentiated into cells producing both IL-17 and IFN-γ in a tumor microenvironment.γδ T cells have emerged as key providers of interleukin 17 (IL-17) in various models of infection, inflammation and autoimmunity [1][2][3][4][5][6] . Antibody-mediated or genetic depletion of γδ T cells greatly reduces disease severity in IL-17-driven models of chronic inflammation [1][2][3][4]7 . Those results notwithstanding, many reports have made a compelling case for γδ T cells as the main producers of interferon-γ (IFN-γ) in both mice and humans 8 , which has been a major foundation for clinical trials targeting these lymphocytes in cancer immunotherapy 9 . Given the dual ability of γδ cells to produce IL-17 and IFN-γ, published work has aimed to contributed to designing the study and writing the manuscript; A.Q.G. helped to design and supervise the study; and B.S.-S. designed and supervised the study and wrote the manuscript. COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests.Reprints and permissions information is available online at http://www.nature.com/reprints/index.html. Europe PMC Funders GroupAuthor Manuscript Nat Immunol. Author manuscript; available in PMC 2016 April 18. Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts identify markers that associate with functional attributes of mouse γδ T cells [10][11][12][13] . Expression of the costimulatory receptor CD27 segregates IL-17-producing (CD27 − ) γδ T cells and IFN-γ-producing (CD27 + ) γδ T cells in both naive and Plasmodium-infected C57BL/6 mice 10 . Moreover, the chemokine receptor CCR6, which is expressed exclusively on CD27 − γδ T cells, constitutes an additional marker for IL-17 + γδ T cells 13,14. Both CD27 + and CD27 − γδ T cell subsets show spontaneous cytokine secretion after activation, in contrast to the delayed differentiation of conventional CD4 + T cells of the T H 1 or T H 17 subset of helper T cells 15 . That finding is highlighted by the observation that 30-40% of peripheral γδ T cells freshly isolated from naive mice produce either IL-17 or IFN-γ after 3 h of restimulation in vitro 10 . Those functionally mature γδ T cell subsets are also found in the thymus, as early as the embryonic stages of mouse development [10][11][12]16 . Moreove...

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that can detect bacteria-derived metabolites presented on MR1. Here we show, using a controlled infection of humans with live Salmonella enterica serovar Paratyphi A, that MAIT cells are activated during infection, an effect maintained even after antibiotic treatment. At the peak of infection MAIT cell T-cell receptor (TCR)β clonotypes that are over-represented prior to infection transiently contract. Select MAIT cell TCRβ clonotypes that expand after infection have stronger TCR-dependent activation than do contracted clonotypes. Our results demonstrate that host exposure to antigen may drive clonal expansion of MAIT cells with increased functional avidity, suggesting a role for specific vaccination strategies to increase the frequency and potency of MAIT cells to optimize effector function.