Human Vγ9Vδ2 T cells exert anti-tumor activity independently of PD-L1 expression in tumor cells

Tomogane, Mako; Sano, Yusuke; Shimizu, Daiki; Shimizu, Teruki; Miyashita, Masatsugu; Toda, Yuki; Hosogi, Shigekuni; Tanaka, Yoshimasa; Kimura, Shinya; Ashihara, Eishi

doi:10.1016/j.bbrc.2021.08.005

Cited by 20 publications

(28 citation statements)

References 25 publications

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“…Vg2 x PD-L1 preserved high affinity to PD-L1 as well as the PD1/PD-L1 blocking activity. However, consistent with other reports, the PD-1/PD-L1 blocking activity did not contribute to the killing ability of Vg2Vd2 T cells (12), possibly because the PD-L1 mAb used in our study contained silent Fc without ADCC capability. Vg2 x PD-L1 had a slower affinity for the Vg2 TCR than Vg2 mAb, which was desired for clinical use to prevent cytokine release storm (35).…”

Section: Discussionsupporting

confidence: 92%

“…Several groups proposed a combination approach of the Vg2Vd2 T cell-based adoptive immunotherapy with a PD-1 checkpoint blockade for the immunity against leukemia (9), follicular lymphoma (10), and prostate cancer (11). Likely, the anti-PD-L1 mAb enhances the cytotoxicity of Vg2Vd2 T cells against PD-L1 high cancer cells by adding ADCC activity (12).…”

Section: Introductionmentioning

confidence: 99%

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Vγ2 x PD-L1, a Bispecific Antibody Targeting Both the Vγ2 TCR and PD-L1, Improves the Anti-Tumor Response of Vγ2Vδ2 T Cell

Yang

Zhou

et al. 2022

Front. Immunol.

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The potent cytotoxic property of Vγ2Vδ2 T cells makes them attractive for adoptive T cell transfer therapy. The transfusing of the expanded Vγ2Vδ2 T cells into cancer patients shows well-tolerated, but the clinical response rates are required to be improved, implying that there is still an unmet efficacy with low toxicity for this novel anti-tumor therapy. In this study, we test the anti-tumor efficacy of a Y-body-based bispecific antibody (bsAb) Vγ2 x PD-L1 that preferentially redirects Vγ2Vδ2 T cells to combat PD-L1 positive tumor cells. With nanomolar affinity levels to Vγ2Vδ2 T cells and PD-L1+ tumor cells, Vγ2 x PD-L1 bridges a Vγ2Vδ2 T cell with a SKOV3 tumor cell to form a cell-to-cell conjugation. In a PD-L1-dependent manner, the bsAb elicits effective activation (CD25+CD69+), IFNγ releasing, degranulation (CD107a+), and cytokine production (IFNγ+ and TNFα+) of expanded Vγ2Vδ2 T cells. The activations of the Vγ2Vδ2 T cells eliminate PD-L1-expressing human cancer cell lines, including H1975, SKOV3, A375, H1299, and H2228 cells, but not PD-L1 negative cells including HEK-293 (293) cells and healthy PBMCs. Finally, we show that combining Vγ2 x PD-L1 with adoptively transferring Vγ2Vδ2 T cells inhibits the growth of existing tumor xenografts and increases the number of Vγ2Vδ2 T cells into the tumor bed. Vγ2 x PD-L1 represents a promising reagent for increasing the efficacy of adoptively transferred Vγ2Vδ2 T cells in the treatment of PD-L1 positive malignant tumors.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Vγ2 x PD-L1, a Bispecific Antibody Targeting Both the Vγ2 TCR and PD-L1, Improves the Anti-Tumor Response of Vγ2Vδ2 T Cell

Yang

Zhou

et al. 2022

Front. Immunol.

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“…The faceted roles of γδ T cells in cancer are shaped by multiple regulators that determine whether they take on a pro- or anti-tumour role, very much depending on their initial effector type programming [ 33 , 34 , 35 ], the tumour microenvironmental context [ 36 , 37 , 38 ], encounters with other tumour-associated immune cells [ 39 , 40 ] and the tumour entities themselves [ 41 , 42 ]. Indeed, γδ T cells are critical cells in cancer as well as in general immunity [ 2 , 43 ]; they are the first T cells to develop [ 44 ], leave the embryonic thymus and home to their target tissues [ 45 ].…”

Section: Functional γδ T-cell Subsets In Mice and Humansmentioning

confidence: 99%

“…For example, as a strategy to boost the anti-tumour activity of Vγ9Vδ2 T cells, the use of PD-1 blockade in conjunction with PAg stimulation has been employed [ 196 , 197 ], aiming to neutralise the effect of the PAg stimulation-related upregulation of PD-1 on γδ T cells [ 198 ]. Interestingly, while use of anti-PD-L1 antibodies was found to indeed increase the anti-tumour effect of γδ T cells [ 41 , 194 ], this was not mediated by an increase in γδ T-cell cytotoxic activity, but rather by γδ T-cell-mediated ADCC induced by the tumour-targeting antibody [ 41 ]. On the other hand, PD-1 blockade was shown to significantly increase IFN-γ production in γδ T cells, although this required the prior activation of γδ T cells or sensitisation of target cells [ 199 ].…”

Section: Pro-tumour Functions Of γδ T Cellsmentioning

confidence: 99%

The Diverse Roles of γδ T Cells in Cancer: From Rapid Immunity to Aggressive Lymphoma

Schönefeldt

Wais

Herling

et al. 2021

Cancers

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γδ T cells are unique players in shaping immune responses, lying at the intersection between innate and adaptive immunity. Unlike conventional αβ T cells, γδ T cells largely populate non-lymphoid peripheral tissues, demonstrating tissue specificity, and they respond to ligands in an MHC-independent manner. γδ T cells display rapid activation and effector functions, with a capacity for cytotoxic anti-tumour responses and production of inflammatory cytokines such as IFN-γ or IL-17. Their rapid cytotoxic nature makes them attractive cells for use in anti-cancer immunotherapies. However, upon transformation, γδ T cells can give rise to highly aggressive lymphomas. These rare malignancies often display poor patient survival, and no curative therapies exist. In this review, we discuss the diverse roles of γδ T cells in immune surveillance and response, with a particular focus on cancer immunity. We summarise the intriguing dichotomy between pro- and anti-tumour functions of γδ T cells in solid and haematological cancers, highlighting the key subsets involved. Finally, we discuss potential drivers of γδ T-cell transformation, summarising the main γδ T-cell lymphoma/leukaemia entities, their clinical features, recent advances in mapping their molecular and genomic landscapes, current treatment strategies and potential future targeting options.

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“…The combination of adoptive γδ T cells plus immune checkpoint inhibitors is a hopeful strategy for improving their cytotoxicity because PAgs-stimulated γδ T cells express PD-1 [117] and Rossi et al reported that blockade of PD-1 can boost antitumor effect of γδ T cells against follicular lymphoma [118]. However, we recently reported that PD-1 blockade did not increase the cytotoxicity of γδ T cell against PD-L1 high solid cancer cells and PD-L1 knockdown did not increase the cytotoxicity [119]. The augmentation effect of blockade of PD-1/PD-L1 axis is still controversial.…”

Section: The Tumor Microenvironment (Tme) Limits the Cytotoxicity Of γδ T Cells By Promoting Their Regulatory Functions By Secreting Immumentioning

confidence: 81%

Strategies to Improve the Antitumor Effect of γδ T Cell Immunotherapy for Clinical Application

Miyashita

Shimizu

Ashihara

et al. 2021

IJMS

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Human γδ T cells show potent cytotoxicity against various types of cancer cells in a major histocompatibility complex unrestricted manner. Phosphoantigens and nitrogen-containing bisphosphonates (N-bis) stimulate γδ T cells via interaction between the γδ T cell receptor (TCR) and butyrophilin subfamily 3 member A1 (BTN3A1) expressed on target cells. γδ T cell immunotherapy is classified as either in vivo or ex vivo according to the method of activation. Immunotherapy with activated γδ T cells is well tolerated; however, the clinical benefits are unsatisfactory. Therefore, the antitumor effects need to be increased. Administration of γδ T cells into local cavities might improve antitumor effects by increasing the effector-to-target cell ratio. Some anticancer and molecularly targeted agents increase the cytotoxicity of γδ T cells via mechanisms involving natural killer group 2 member D (NKG2D)-mediated recognition of target cells. Both the tumor microenvironment and cancer stem cells exert immunosuppressive effects via mechanisms that include inhibitory immune checkpoint molecules. Therefore, co-immunotherapy with γδ T cells plus immune checkpoint inhibitors is a strategy that may improve cytotoxicity. The use of a bispecific antibody and chimeric antigen receptor might be effective to overcome current therapeutic limitations. Such strategies should be tested in a clinical research setting.

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Human Vγ9Vδ2 T cells exert anti-tumor activity independently of PD-L1 expression in tumor cells

Cited by 20 publications

References 25 publications

Vγ2 x PD-L1, a Bispecific Antibody Targeting Both the Vγ2 TCR and PD-L1, Improves the Anti-Tumor Response of Vγ2Vδ2 T Cell

Vγ2 x PD-L1, a Bispecific Antibody Targeting Both the Vγ2 TCR and PD-L1, Improves the Anti-Tumor Response of Vγ2Vδ2 T Cell

The Diverse Roles of γδ T Cells in Cancer: From Rapid Immunity to Aggressive Lymphoma

Strategies to Improve the Antitumor Effect of γδ T Cell Immunotherapy for Clinical Application

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