Ex vivo characterization of γδ T-cell repertoire in patients after adoptive transfer of Vγ9Vδ2 T cells expressing the interleukin-2 receptor β-chain and the common γ-chain

Izumi, Takamichi; Kondo, Makoto; Takahashi, Takuya; Fujieda, Nao; Kondo, Atsushi; Tamura, Naohisa; Murakawa, Tomohiro; Nakajima, Jun; Matsushita, Hirokazu; Kakimi, Kazuhiro

doi:10.1016/j.jcyt.2012.12.004

Cited by 67 publications

(50 citation statements)

References 28 publications

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“…However, we and others have shown that the PDA TME is rife with TGF-β which can possibly induce FoxP3 expression (Goggins et al, 1998; Greco et al, 2015). Also consistent with a tumor-permissive phenotype, human PDA-infiltrating γδT cells do not express the Vγ9 TCR whose ligation has been implicated in the direct tumoricidal activity of γδT cells in melanoma and colon cancer (Izumi et al, 2013; Kunzmann et al, 2012). …”

Section: Discussionmentioning

confidence: 90%

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γδ T Cells Support Pancreatic Oncogenesis by Restraining αβ T Cell Activation

Daley

Zambirinis

Seifert

et al. 2016

Cell

262

252

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Summary Inflammation is paramount in pancreatic oncogenesis. We identified a uniquely-activated γδT cell population which constituted ∼40% of tumor-infiltrating T cells in human pancreatic ductal adenocarcinoma (PDA). Recruitment and activation of γδT cells was contingent on diverse chemokine signals. Deletion, depletion, or blockade of γδT cell recruitment was protective against PDA and resulted in increased infiltration, activation, and Th1-polarization of αβT cells. Whereas αβT cells were dispensable to outcome in PDA, they became indispensable mediators of tumor-protection upon γδT cell ablation. PDA-infiltrating γδT cells expressed high levels of exhaustion ligands and thereby negated adaptive anti-tumor immunity. Blockade of PD-L1 in γδT cells enhanced CD4+ and CD8+ T cell infiltration and immunogenicity and induced tumor-protection suggesting that γδT cells are critical sources of immune-suppressive checkpoint ligands in PDA. We describe γδT cells as central regulators of effector T cell activation in cancer via novel cross-talk.

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Section: Discussionmentioning

confidence: 90%

“…Accordingly, tumor-infiltrating γδT cells down-regulated CD62L compared with their counterparts in PBMC (Figure 1f). However, Vγ9 + γδT cells – associated with tumoricidal function (Izumi et al, 2013; Kunzmann et al, 2012) – were notably absent in PDA, suggestive of tumor-permissive properties (Figure 1g). …”

Section: Resultsmentioning

confidence: 99%

γδ T Cells Support Pancreatic Oncogenesis by Restraining αβ T Cell Activation

Daley

Zambirinis

Seifert

et al. 2016

Cell

262

252

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“…Expression of IL-15 was important for the maintenance of transferred γδT cells in vivo (48), supporting the use of IL-15 on aAPC, and future studies could inform on other molecules that could be introduced to maximize the cell therapy product. Correlative studies are enhanced by our observation that TCRγδmAb can be used to readily distinguish the three (Vδ1, Vδ2, and Vδ1 neg Vδ2 neg ) T-cell subsets based on MFI of TCRγδexpression (Figure 3B).…”

Section: Discussionmentioning

confidence: 94%

Activating and Propagating Polyclonal Gamma Delta T Cells with Broad Specificity for Malignancies

Deniger¹,

Maiti²,

Mi³

et al. 2014

Clinical Cancer Research

101

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Purpose To activate and propagate populations of γδT cells expressing polyclonal repertoire of γ and δ TCR chains for adoptive immunotherapy for cancer, which has yet to be achieved. Experimental Design Clinical-grade artificial antigen presenting cells (aAPC) derived from K562 tumor cells were used as irradiated feeders to activate and expand human γδT cells to clinical scale. These cells were tested for proliferation, TCR expression, memory phenotype, cytokine secretion, and tumor killing. Results γδT cell proliferation was dependent upon CD137L expression on aAPC and addition of exogenous IL-2 and IL-21. Propagated γδT cells were polyclonal as they expressed Vδ1, Vδ2, Vδ3, Vδ5, Vδ7, and Vδ8 with Vγ2, Vγ3, Vγ7, Vγ8, Vγ9, Vγ10, and Vγ11 TCR chains. Interferon-γ production by Vδ1, Vδ2, and Vδ1negVδ2neg subsets was inhibited by pan-TCRγδantibody when added to co-cultures of polyclonal γδT cells and tumor cell lines. Polyclonal γδT cells killed acute and chronic leukemia, colon, pancreatic, and ovarian cancer cell lines, but not healthy autologous or allogeneic normal B cells. Blocking antibodies demonstrated that polyclonal γδT cells mediated tumor cell lysis through combination of DNAM1, NKG2D, and TCRγδ. The adoptive transfer of activated and propagated γδT cells expressing polyclonal versus defined Vδ TCR chains imparted a hierarchy (polyclonal>Vδ1>Vδ1negVδ2neg>Vδ2) of survival of mice with ovarian cancer xenografts. Conclusions Polyclonal γδT cells can be activated and propagated with clinical-grade aAPC and demonstrate broad anti-tumor activities, which will facilitate the implementation of γδT cell cancer immunotherapies in humans.

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“…The absolute numbers of Vg9Vd2 T cells within these sites, at different time points after injection, were not determined, which did not allow us to state the effective growth or survival of injected human gd T cells. Interestingly, a recent study has shown that, in patients with advanced colorectal cancer who received weekly injections of autologous Vg9Vd2 T cells, the frequency and absolute number of peripheral gd T cells gradually increased during the course of treatment (40). Surprisingly, functionally active Vg9Vd2 T cells persisted for a prolonged period after the last infusions, even in the absence of exogenous rhIL-2.…”

Section: Discussionmentioning

confidence: 99%

Repeated Systemic Administrations of Both Aminobisphosphonates and Human Vγ9Vδ2 T Cells Efficiently Control Tumor Development In Vivo

Santolaria

Robard

Léger

et al. 2013

The Journal of Immunology

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Peripheral Vγ9Vδ2 T lymphocytes compose a major γδ T cell subset in primates with broad reactivity against tumor cells. Vγ9Vδ2 T cells are specifically activated by phosphorylated isoprenoid pathway metabolites called “phosphoagonists.” Accordingly, pharmacologic inhibitors of the mevalonate pathway, such as aminobisphosphonates (NBP) that upregulate the intracellular production of phosphoagonists, increase antitumor Vγ9Vδ2 T cell responses. Immunotherapeutic protocols exploiting GMP-grade agonist molecules targeting human Vγ9Vδ2 T lymphocytes have yielded promising, yet limited, signs of antitumor efficacy and therefore need to be improved for next-generation immunotherapies. In this study, we used a model of s.c. human tumor xenografts in severely immunodeficient mice to assess the antitumor efficacy of systemic NBP treatments when combined with the adoptive transfer of human Vγ9Vδ2 T cells. We show that infusion of Vγ9Vδ2 T cells, 24 h after systemic NBP treatment, efficiently delays tumor growth in mice. Importantly, our results indicate efficient but transient in vivo NBP-induced sensitization of tumor cells to human Vγ9Vδ2–T cell recognition. Accordingly, repeated and combined administrations of both NBP and γδ T cells yielded improved antitumor responses in vivo. Because Vγ9Vδ2 T cells show similar responsiveness toward both autologous and allogeneic tumors and are devoid of alloreactivity, these results provide preclinical proof of concept for optimized antitumor immunotherapies combining NBP treatment and adoptive transfer of allogeneic human γδ T cells.

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Ex vivo characterization of γδ T-cell repertoire in patients after adoptive transfer of Vγ9Vδ2 T cells expressing the interleukin-2 receptor β-chain and the common γ-chain

Cited by 67 publications

References 28 publications

γδ T Cells Support Pancreatic Oncogenesis by Restraining αβ T Cell Activation

γδ T Cells Support Pancreatic Oncogenesis by Restraining αβ T Cell Activation

Activating and Propagating Polyclonal Gamma Delta T Cells with Broad Specificity for Malignancies

Repeated Systemic Administrations of Both Aminobisphosphonates and Human Vγ9Vδ2 T Cells Efficiently Control Tumor Development In Vivo

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