Harnessing γδ T cells in anticancer immunotherapy

Hannani, Dalil; Ma, Yuting; Yamazaki, Takahiro; Déchanet‐Merville, Julie; Kroemer, Guido; Zitvogel, Laurence

doi:10.1016/j.it.2012.01.006

Cited by 98 publications

(96 citation statements)

References 80 publications

(94 reference statements)

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“…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)(14)(15). There is therefore great interest in maximizing the antitumor functions of γδ T cells for cancer immunotherapy.…”

Section: Gamma-delta T Cells | Tumor Immunologymentioning

confidence: 99%

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

Rei

Gonçalves-Sousa

Lança

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

179

199

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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 ...

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Section: Gamma-delta T Cells | Tumor Immunologymentioning

confidence: 99%

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

Rei

Gonçalves-Sousa

Lança

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

179

199

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“…The primary reasons for involving cd cell activation in cancer therapies will be summarized below only briefly, as this topic has recently been reviewed. [1][2][3][4] First, the hallmark characteristic of T lymphocytes expected to interact with cancer cells is their capacity to infiltrate tumors. Accordingly, tumor-infiltrating gamma delta T lymphocytes (cd TILs) were detected in a broad spectrum of malignancies.…”

Section: Rationale For Harnessing CD Cells In Cancer Immunotherapymentioning

confidence: 99%

What lessons can be learned from γδ T cell-based cancer immunotherapy trials?

et al. 2012

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During the last several years, research has produced a significant amount of knowledge concerning the characteristics of human cd T lymphocytes. Findings regarding the immune functions of these cells, particularly their natural killer cell-like lytic activity against tumor cells, have raised expectations for the therapeutic applications of these cells for cancer. Pharmaceutical companies have produced selective agonists for these lymphocytes, and several teams have launched clinical trials of cd T cell-based cancer therapies. The findings from these studies include hematological malignancies (follicular lymphoma, multiple myeloma, acute and chronic myeloid leukemia), as well as solid tumors (renal cell, breast and prostate carcinomas), consisting of samples from more than 250 patients from Europe, Japan and the United States. The results of these pioneering studies are now available, and this short review summarizes the lessons learned and the role of cd T cell-based strategies in the current landscape of cancer immunotherapies.

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“…1,2 Due to their peculiar antigen recognition and mechanism of activation, all gd T cells are thought to participate in anti-tumor surveillance in several cancer types, including hematologic malignancies. 6,8,[13][14][15][16][17][18] Moreover, different drugs can be exploited to enhance each mechanism of gd T-cell activation. First, aminobisphosphonates (N-BPs) commonly used to treat bone diseases and hypercalcemia in myeloma patients, have been shown to activate Vd2 T cells by blocking protein prenylation along the cholesterol synthesis pathway and accumulating phosphorylated metabolites.…”

Section: Introductionmentioning

confidence: 99%

“…12,19,27 In this regard, we and others have described that gd T lymphocytes are involved in the surveillance against acute myeloid leukemias, multiple myeloma, CLL, Hodgkin's (HL) and non-Hodgkin's lymphomas (NHL) [13][14][15][16][17][18][19][20][21][22][23][24][25][26] by the means of one or another of the abovementioned mechanisms (i.e. PAg recognition, cytotoxicity of targets expressing stress-related molecules, ADCC).…”

Section: Introductionmentioning

confidence: 99%

Aminobisphosphonates prevent the inhibitory effects exerted by lymph node stromal cells on anti-tumor V 2 T lymphocytes in non-Hodgkin lymphomas

et al. 2013

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Harnessing γδ T cells in anticancer immunotherapy

Cited by 98 publications

References 80 publications

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

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

What lessons can be learned from γδ T cell-based cancer immunotherapy trials?

Aminobisphosphonates prevent the inhibitory effects exerted by lymph node stromal cells on anti-tumor V 2 T lymphocytes in non-Hodgkin lymphomas

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Harnessing γδ T cells in anticancer immunotherapy

Cited by 98 publications

References 80 publications

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

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

What lessons can be learned from γδ T cell-based cancer immunotherapy trials?

Aminobisphosphonates prevent the inhibitory effects exerted by lymph node stromal cells on anti-tumor V 2 T lymphocytes in non-Hodgkin lymphomas

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

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