Strategies to Improve the Antitumor Effect of γδ T Cell Immunotherapy for Clinical Application |
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Authors: | Masatsugu Miyashita Teruki Shimizu Eishi Ashihara Osamu Ukimura |
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Affiliation: | 1.Department of Urology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; (T.S.); (O.U.);2.Department of Urology, Japanese Red Cross Kyoto Daini Hospital, Kyoto 602-8026, Japan;3.Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan; |
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Abstract: | 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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Keywords: | γ δ T cells, immunotherapy, tumor resistance, combination therapy, tumor microenvironment, immune checkpoint inhibitor |
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