Phosphoantigens Overcome Human TCRVγ9+ γδ Cell Immunosuppression by TGF-β: Relevance for Cancer Immunotherapy

Capietto, Aude-Hélène; Martinet, Ludovic; Cendron, Delphine; Fruchon, Séverine; Pont, Frédéric; Fournié, Jean‐Jacques

doi:10.4049/jimmunol.1000681

Cited by 25 publications

(27 citation statements)

References 79 publications

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“…In our report, CD103 + Vd2T cells were less responsive to phosphoantigen, produced lower levels of inflammatory cytokines, and failed to enhance conventional T cell responses. If CD103 expression by Vd2T cells is a consequence of exposure to TGF-b, then this anti-inflammatory mediator may also be responsible for blunting production of IFN-g and TNF-a in the CD103 + subset (52). Impaired TGF-b signaling has already been identified among mucosal abT cells in CD (53); therefore, the altered function of CD103 + Vd2T cells warrants further analysis in the CD intestine.…”

Section: Discussionmentioning

confidence: 99%

Proinflammatory Vδ2+ T Cells Populate the Human Intestinal Mucosa and Enhance IFN-γ Production by Colonic αβ T Cells

McCarthy

Bashir

Vossenkämper

et al. 2013

The Journal of Immunology

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In nonhuman primates, Vγ9Vδ2+ (Vδ2)T cells proliferate and accumulate in mucosal tissues following microbial activation. Human Vδ2T cells produce proinflammatory cytokines in response to bacterial species that colonize the gut, but the role played by Vδ2T cells in intestinal immunity is unknown. We hypothesized that circulating Vδ2T cells can populate the human intestine and contribute to mucosal inflammation. Cell suspensions prepared from peripheral blood and intestinal biopsies were stimulated with microbial phosphoantigen (1-hydroxy-2-methyl-2-buten-4-yl 4-diphosphate [HDMAPP]) and analyzed by flow cytometry to determine Vδ2T cell phenotype, cytokine production, and proliferative potential. Circulating Vδ2T cells expressed gut-homing integrin α4β7 (>70%), which was coexpressed with skin-associated cutaneous leukocyte Ag by up to 15% of the total population. However, Vδ2T cell activation with HDMAPP and exposure to retinoic acid (signaling via retinoic acid receptor α) increased α4β7 expression and enhanced binding to mucosal addressin cell adhesion molecule-1 in vitro while simultaneously suppressing cutaneous leukocyte Ag, thereby generating a committed gut-tropic phenotype. Confocal microscopy and flow cytometry identified frequent Vδ2T cells that migrated out of human intestinal biopsies and comprised both CD103+ and CD103− subsets that produced TNF-α and IFN-γ upon phosphoantigen exposure, with more frequent cytokine-producing cells in the CD103− population. Activated intestinal Vδ2T cells expressed CD70 and HLA-DR but were unable to drive the proliferation of allogeneic naive CD4+ T cells. Instead, phosphoantigen-activated CD103− Vδ2T cells increased T-bet expression and enhanced IFN-γ production by autologous colonic αβ T cells via an IFN-γ–dependent mechanism. These data demonstrate that circulating Vδ2T cells display enhanced gut-homing potential upon microbial activation and populate the human intestinal mucosa, generating functionally distinct CD103+ and CD103− subsets that can promote inflammation by colonic αβ T cells.

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Section: Discussionmentioning

confidence: 99%

Proinflammatory Vδ2+ T Cells Populate the Human Intestinal Mucosa and Enhance IFN-γ Production by Colonic αβ T Cells

McCarthy

Bashir

Vossenkämper

et al. 2013

The Journal of Immunology

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“…47,48 The reverse situation, however, might also occur in these patients, as phosphoantigen-activated cd T cells can overcome Tregs 49 and TGF-b immunosuppressive functions. 50 The above trials demonstrated that Tregs were not significantly induced by these regimens involving only low doses of IL-2, and they did not offer evidence of Treg-based cd T-cell immunosuppression. Therefore, although the utilization of IL-2 in these trials was a concern, its use did not hamper clinical responses.…”

Section: Safety Of CD T-cell Activation In Patientsmentioning

confidence: 93%

“…The in vitro bioactivity of BrHPP (EC 50 ) is 24/nM for TCRVc9Vd2 1 T-cell clones and peripheral blood mononuclear cells, 30 and this drug is produced as Good Manufacture Practice grade for use in humans under the name Phosphostim/IPH1101 (Innate Pharma, France). Zoledronate, a third generation aminobisphosphonate inhibitor of farnesyl pyrophosphate synthase that has been used for osteolysis (Novartis, Switzerland), induces bioaccumulation of endogenous phosphoantigens.…”

Section: Rationale For Harnessing CD Cells In Cancer Immunotherapymentioning

confidence: 99%

“…The potent immunosuppressor TGF-b, which is frequently secreted by human cancers, is capable of repressing cytotoxic immune responses, although the bioactivity of this molecule can be counterbalanced by augmenting its activation with phosphoantigens. 50 There are currently few case reports, however, depicting a tumor cell relapse following a therapeutic response to cd T cell-based immunotherapy. Nevertheless, the aforementioned trials only involved patients with advanced and relapsing metastatic renal cancers, prostate cancer and B-cell lymphomas.…”

Section: Safety Of CD T-cell Activation In Patientsmentioning

confidence: 99%

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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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“…[3][4][5][6][7][8] Different drugs can be utilized to improve the mechanisms of gd T cell activation: 2,3,8 in particular, synthetic pyrophosphate-containing compounds have been proposed for cancer immunotherapy on the basis of their ability to stimulate gdT cells. [9][10][11][12] Moreover, aminobisphosphonates (N-BPs), in addition to their effect of inhibiting osteoclastic bone resorption, 13 lead to gd T cell activation and proliferation, with a consequent increased number of gd T cells in peripheral blood, displaying antitumor activity [14][15][16][17][18] Indeed, N-BPs, such as zoledronate (Zol), are chemically stable analogs of inorganic pyrophosphate (IPP) that inhibit the mevalonate pathway and upregulate IPP accumulation, promoting antitumor Vg9Vd2 T cells in vitro and in vivo. [15][16][17][18][19][20] For this reason, different N-BPs have been used in anticancer clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Zoledronate can induce colorectal cancer microenvironment expressing BTN3A1 to stimulate effector γδ T cells with antitumor activity

et al. 2017

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Amino-bis-phosphonates (N-BPs) such as zoledronate (Zol) have been used in anticancer clinical trials due to their ability to upregulate pyrophosphate accumulation promoting antitumor Vg9Vd2 T cells. The butyrophilin 3A (BTN3A, CD277) family, mainly the BTN3A1 isoform, has emerged as an important structure contributing to Vg9Vd2 T cells stimulation. It has been demonstrated that the B30.2 domain of BTN3A1 can bind phosphoantigens (PAg) and drive the activation of Vg9Vd2 T cells through conformational changes of the extracellular domains. Moreover, BTN3A1 binding to the cytoskeleton, and its consequent membrane stabilization, is crucial to stimulate the PAg-induced tumor cell reactivity by human Vg9Vd2 T cells. Aim of this study was to investigate the relevance of BTN3A1 in N-BPs-induced antitumor response in colorectal cancer (CRC) and the cell types involved in the tumor microenvironment.In this paper, we show that (i) CRC, exposed to Zol, stimulates the expansion of Vd2 T lymphocytes with effector memory phenotype and antitumor cytotoxic activity, besides sensitizing cancer cells to gd T cellmediated cytotoxicity; (ii) this effect is partially related to BTN3A1 expression and in particular with its cellular re-distribution in the membrane and cytoskeleton-associated fraction; (iii) BTN3A1 is detected in CRC at the tumor site, both on epithelial cells and on tumor-associated fibroblasts (TAF), close to areas infiltrated by Vd2 T lymphocytes; (iv) Zol is effective in stimulating antitumor effector Vd2 T cells from exvivo CRC cell suspensions; and (v) both CRC cells and TAF can be primed by Zol to trigger Vd2 T cells.

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Phosphoantigens Overcome Human TCRVγ9+ γδ Cell Immunosuppression by TGF-β: Relevance for Cancer Immunotherapy

Cited by 25 publications

References 79 publications

Proinflammatory Vδ2+ T Cells Populate the Human Intestinal Mucosa and Enhance IFN-γ Production by Colonic αβ T Cells

Proinflammatory Vδ2+ T Cells Populate the Human Intestinal Mucosa and Enhance IFN-γ Production by Colonic αβ T Cells

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

Zoledronate can induce colorectal cancer microenvironment expressing BTN3A1 to stimulate effector γδ T cells with antitumor activity

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