Anti-PD-1 antibody armored γδ T cells enhance anti-tumor efficacy in ovarian cancer

γδ T cells have the unique ability to detect a wide range of tumors with low mutation burdens,making them attractive candidates for CAR-T-cell therapy.Unlike aβT cells and other immune cells,γδ T cells are superior in MHC non-restriction,selective cell recruitment,and rapid activation.However,clinical trials have shown limited clinical benefits,and the adoptive transplantation of γδ T cells has often fallen short of expectations.We hypothesized that the limited effectiveness of γδ T cells in eradicating tumor cells may be attributed to the inhibitory tumor microenvironment induced by the suppressive PD-1/PD-L1 axis.Herein,we constructed novel armored γδ T cells capable of secreting humanized anti-PD-1 antibodies,referred to as"Lv-PD1-ys T cells.Lv-PD1-γδ T cells showed improved proliferation and enhanced cytotoxicity against tumor cells,resulting in augmented therapeutic effects and survival benefits in ovarian tumor-bearing mice.These engineered cells demonstrated a prolonged in vivo survival of more than 29 days,without any potential for tumorigenicity in immunodeficient NOD/SCID/null mice.We also found that Lv-PD1-γδ T cells exhibited excellent tolerance and safety in humanized NOD/SCID/null mice.With attenuated or eliminated immunosuppression and maximized cytotoxicity efficacy by the local secretion of anti-PD1 antibodies in tumors,Lv-PD1-γδ T cells can serve as a promising"off-the-shelf"cell therapy against cancers.