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

Human gamma delta 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 gamma delta T cells via interaction between the gamma delta T cell receptor (TCR) and butyrophilin subfamily 3 member A1 (BTN3A1) expressed on target cells. gamma delta T cell immunotherapy is classified as either in vivo or ex vivo according to the method of activation. Immunotherapy with activated gamma delta T cells is well tolerated; however, the clinical benefits are unsatisfactory. Therefore, the antitumor effects need to be increased. Administration of gamma delta 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 gamma delta 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 gamma delta 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.

Automated summary

Human gamma delta T cells exhibit potent cytotoxicity against various types of cancer cells in an MHC-unrestricted manner. Activation of gamma delta T cells can be achieved via phosphoantigens and N-bis interacting with BTN3A1 on target cells. Co-immunotherapy with gamma delta T cells and immune checkpoint inhibitors may enhance cytotoxicity against cancer cells. Strategies such as the use of bispecific antibodies and chimeric antigen receptors should be further studied in a clinical research setting to overcome current therapeutic limitations.