Murine CD27 ⁽⁻⁾ Vγ6 ⁽⁺⁾ γδ T cells producing IL-17A promote ovarian cancer growth via mobilization of protumor small peritoneal macrophages

Abstract

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 ...

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

“…Pro‐tumour function of γδ 17 cells has been demonstrated in several cancer models, including a breast cancer metastasis model72 and an ovarian cancer model,73 and the roles of γδ 17 cells in the development of tumours have been reviewed elsewhere 74. Abundant γδ 17 cell infiltration accompanied by immunosuppressive myeloid‐derived suppressor cells is found in human colorectal cancer with positive correlation with advanced tumour clinicopathological features, suggesting that γδ 17 cells induce myeloid‐derived suppressor cell‐mediated immunosuppression 75.…”

γδTCR recruits the Syk/PI3K axis to drive proinflammatory differentiation program

“…A subset of γδT cells that produces IL-17 (termed γδT17 cells) plays a pivotal role not only in protection against bacterial and fungal infection (1) but also in the progression of inflammatory disorders (2-4), tumor growth and metastasis (5)(6)(7)(8), and tissue regeneration (9). The cytokine-producing potential of γδT cells is programmed during their development in the thymus (10,11).…”

Characterization of γδ T cells in patients with non-small cell lung cancer

“…A previous study suggested that TCRγδ-deficient mice display reduced tumor growth compared with wild-type animals (35). The different levels of CD3 and TCRγδ expression may indicate that in these two subsets, a variety of co-stimulatory signaling pathways could be involved in the regulation of activation and proliferation.…”