AUTHOR=Pei Yujun , Xiang Zheng , Wen Kun , Tu Chloe Ran , Wang Xiwei , Zhang Yanmei , Mu Xiaofeng , Liu Yinping , Tu Wenwei 

TITLE=CD137 Costimulation Enhances the Antitumor Activity of Vγ9Vδ2-T Cells in IL-10-Mediated Immunosuppressive Tumor Microenvironment

JOURNAL=Frontiers in Immunology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.872122

DOI=10.3389/fimmu.2022.872122

ISSN=1664-3224

ABSTRACT=Although γδ-T cell-based tumor immunotherapy by using phosphoantigens to boost γδ-T cell immunity has shown success in some cancer patients, their clinical application is limited due to the rapid exhaustion of Vγ9Vδ2-T cells caused by repetitive stimulation from phosphoantigens and the profoundly immunosuppressive tumor microenvironment (TME). In this study, using cell culture medium containing human and viral interleukin-10 (hIL-10 and vIL-10) secreted from EBV-transformed autologous lymphoblastoid B cell lines (EBV-LCL) to mimic the immunosuppressive TEM, we found that the antitumor activity of Vγ9Vδ2-T cells was highly suppressed by endogenous hIL-10 and vIL-10 within the TME. CD137 costimulation could provide an anti-exhaustion signal to mitigate the suppressive effects of IL-10 in TME through suppressing IL-10R1 expression on Vγ9Vδ2-T cells. CD137 costimulation also enhanced the compromised antitumor activity of Vγ9Vδ2-T cells in TME with high levels of IL-10 in Rag2-/- γc-/- mice. In humanized mice reconstituted with human peripheral blood mononuclear cells, CD137 costimulation with a recombinant human CD137L protein boosted the therapeutic effects of aminobisphosphonate pamidronate against EBV-induced lymphoma. Our study provides a novel strategy to overcome the obstacle of the hIL-10 and vIL-10-mediated immunosuppressive microenvironment by targeting CD137 and improve the efficacy of Vγ9Vδ2-T cell-based tumor immunotherapy.