How tumors might withstand γδ T-cell attack

Capietto, Aude-Hélène; Martinet, Ludovic; Fournié, Jean‐Jacques

doi:10.1007/s00018-011-0705-7

Cited by 17 publications

(16 citation statements)

References 122 publications

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“…However, the use of [(Her2) 2 xVg9] could be limited by the suppressive microenvironment of PDAC. One of the defining characteristics of PDAC is the presence of a dense desmoplastic stroma, which comprises of mesenchymal cells such as fibroblasts and pancreatic stellate cells as well as myeloidderived suppressor cells (MDSC) or suppressive tumor-associated macrophages (TAM) preventing the penetration of cytotoxic T-lymphocytes to the tumor site (42)(43)(44). Preliminary experiments demonstrate that enhancement of the cytotoxic potential of gd T cells could overcome suppression by TAMs (unpublished).…”

Section: Discussionmentioning

confidence: 99%

Novel Bispecific Antibodies Increase γδ T-Cell Cytotoxicity against Pancreatic Cancer Cells

Oberg¹,

Peipp²,

Kellner³

et al. 2014

Cancer Research

124

160

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The ability of human gd T cells from healthy donors to kill pancreatic ductal adenocarcinoma (PDAC) in vitro and in vivo in immunocompromised mice requires the addition of gd T-cell-stimulating antigens. In this study, we demonstrate that gd T cells isolated from patients with PDAC tumor infiltrates lyse pancreatic tumor cells after selective stimulation with phosphorylated antigens. We determined the absolute numbers of gd T-cell subsets in patient whole blood and applied a real-time cell analyzer to measure their cytotoxic effector function over prolonged time periods. Because phosphorylated antigens did not optimally enhance gd T-cell cytotoxicity, we designed bispecific antibodies that bind CD3 or Vg9 on gd T cells and Her2/neu (ERBB2) expressed by pancreatic tumor cells. Both antibodies enhanced gd T-cell cytotoxicity with the Her2/Vg9 antibody also selectively enhancing release of granzyme B and perforin. Supporting these observations, adoptive transfer of gd T cells with the Her2/Vg9 antibody reduced growth of pancreatic tumors grafted into SCID-Beige immunocompromised mice. Taken together, our results show how bispecific antibodies that selectively recruit gd T cells to tumor antigens expressed by cancer cells illustrate the tractable use of endogenous gd T cells for immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Novel Bispecific Antibodies Increase γδ T-Cell Cytotoxicity against Pancreatic Cancer Cells

Oberg¹,

Peipp²,

Kellner³

et al. 2014

Cancer Research

124

160

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“…28 Tumor cells, however, exploit different mechanisms to escape gd T cell-mediated antitumor immunity, reviewed by others. 31,32 For example, tumor cells promote gd T cells to adopt a regulatory T cell (Treg) phenotype. Such gd Tregs damp antitumor immunity 33 and contribute to the immunosuppressive microenvironment that is characteristic of most tumor cells.…”

Section: Gd T Cells and Cancer Immunitymentioning

confidence: 99%

Empowering gamma delta T cells with antitumor immunity by dendritic cell-based immunotherapy

Anguille

et al. 2015

OncoImmunology

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These authors equally contributed to the work.Keywords: gd T cell, cancer, DC-mediated gd T cell activation, dendritic cell, immunotherapy Abbreviations: gd, gamma delta; BCG, Bacillus Calmette-Guerin; BrHPP, bromohydrin pyrophosphate; CTL, cytotoxic T lymphocyte; DC, dendritic cell; GM-CSF, granulocyte-macrophage colony-stimulating factor; HIV, human immunodeficiency virus; HMBPP, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate; iDC, immature DC; IFN, interferon; IL, interleukin; IPP, isopentyl pyrophosphate; mDC, myeloid dendritic cell; MHC, major histocompatibility complex; mo-DC, monocyte-derived dendritic cell; pDC, plasmacytoid dendritic cell; PD, programmed cell death protein; TCR, T-cell receptor; Th, T-helper cell; TLR, toll-like receptor; TNF, tumor necrosis factor; Treg, regulatory T cellGamma delta (gd) T cells are the all-rounders of our immune-system with their major histocompatibility complexunrestricted cytotoxicity, capacity to secrete immunostimulatory cytokines and ability to promote the generation of tumor antigen-specific CD8 C and CD4 C T cell responses. Dendritic cell (DC)-based vaccine therapy has the prospective to harness these unique features of the gd T cells in the fight against cancer. In this review, we will discuss our current knowledge on DC-mediated gd T cell activation and related opportunities for tumor immunologists.

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“…Whether PPAR also regulates human  T cell functions remains unclear. PAg-selective desensitization has been identified as a pitfall in the development of V9V2 T cell-based cancer immunotherapy [14,15]. As the first step to elucidate the molecular mechanisms underlying this in vivo desensitization, we analyzed the transcriptome of circulating V9V2 T cells from macaques injected with BrHPP and control subjects that did not receive the injection.…”

Section: Introductionmentioning

confidence: 99%

The PPARα pathway in Vγ9Vδ2 T cell anergy

Poupot

Boissard

Bétous

et al. 2014

Cellular and Molecular Biology Letters

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Phosphoantigens (PAgs) activate V9V2 T lymphocytes, inducing their potent and rapid response in vitro and in vivo. However, humans and nonhuman primates that receive repeated injections of PAgs progressively lose their V9V2 T cell response to them. To elucidate the molecular mechanisms of this in vivo desensitization, we analyzed the transcriptome of circulating V9V2 T cells from macaques injected with PAg. We showed that three PAg injections induced the activation of the PPAR pathway in V9V2 T cells. Thus, we analyzed the in vitro response of V9V2 T cells stimulated with a PPAR agonist. We demonstrated that in vitro PPAR pathway activation led to the inhibition of the BrHPP-induced activation and proliferation of human V9V2 T cells. Since the PPAR pathway is involved in the antigen-selective desensitization of human V9V2 T cells, the use of PPAR inhibitors could enhance cancer immunotherapy based on V9V2 T cells.

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How tumors might withstand γδ T-cell attack

Cited by 17 publications

References 122 publications

Novel Bispecific Antibodies Increase γδ T-Cell Cytotoxicity against Pancreatic Cancer Cells

Novel Bispecific Antibodies Increase γδ T-Cell Cytotoxicity against Pancreatic Cancer Cells

Empowering gamma delta T cells with antitumor immunity by dendritic cell-based immunotherapy

The PPARα pathway in Vγ9Vδ2 T cell anergy

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