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

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.

The Mysterious Actor—γδ T Lymphocytes in Chronic Lymphocytic Leukaemia (CLL)

“…Both Vδ1 and Vδ2 subsets express high cytotoxic potential and are important in cancer immunosurveillance [ 35 , 46 ]. The tumour micro-environment can also promote regulatory functions in γδ T cells, simultaneously lowering their cytotoxic potential [ 47 ].…”

In Acute Dengue Infection, High TIM-3 Expression May Contribute to the Impairment of IFNγ Production by Circulating Vδ2 T Cells

“…γδ T cells play a role in several clinical settings such as autoimmune diseases [8][9][10], allergies [11,12], and cancer [13], and are known to exert a potent antimicrobial activity against both bacterial [14] and viral infections [15,16]. Moreover, human Vδ2 T cells exert their antimicrobial activities through both cytolytic and non-cytolytic mechanisms [16][17][18][19] and can shape several others immune functions (e.g., dendritic cell activation, neutrophil recruitment/activation, Th1 polarization, soluble factor release, and NK-like cytotoxicity) by producing immune-modulating factors [20].…”

γδ T cell costimulatory ligands in antitumor immunity

“…To date, the clinical use of γδ T cell-based immunotherapies has revolved around targeting Vγ9Vδ2 T cell activation via phosphoantigen sensing. Phosphoantigens such as endogenous isopentenyl pyrophosphate (IPP) and the microbial metabolite ( E )-4-hydroxy-3-methyl-but-2-enyl-pyrophosphate (HMB-PP) drive conformational changes in the accessory molecules butyrophilin subfamily 3 member A1 (BTN3A1) and BTN2A1, which are then recognized by Vγ9Vδ2 T cells [ 95 , 96 ]. The roles of butyrophilin molecules in humans and butyrophilin-like molecules in both humans and mice for γδTCR antigen recognition have been reviewed in detail elsewhere [ 97 – 99 ].…”

“…These drugs additionally inhibit the mevalonate pathway resulting in increased intracellular concentrations of IPP allowing for Vγ9Vδ2 T cell activation and expansion in vivo . Alternatively, Vγ9Vδ2 T cells can be expanded ex vivo using either amino-bisphosphonates or often phosphoantigens such as IPP or HMB-PP directly for ACT approaches [ 95 , 101 ]. Vγ9Vδ2 T cells expanded in this way have shown enhanced antitumor activity both in vitro and in preclinical mouse tumor xenograft models [ 102 ].…”

“…As discussed above, the use of γδ T cells in ACT therapies has garnered much interest because of their potential use as an “off-the-self”, allogeneic T cell therapy without the need for donor-recipient MHC matching [ 95 ]. The use of bisphosphonates to expand Vγ9Vδ2 T cells and novel protocols to expand Vδ1 + T cells may prove to be effective immunotherapies, but there is likely much room for improvement in the engineering of these T cell products.…”