Lactate conditioning reprograms mucosal-associated invariant T cell metabolism boosting effector function

Mucosal-associated invariant T (MAIT) cells are unconventional T cells, which upon activation can display potent cytotoxic and cytokine-producing capabilities. Together, these features make MAIT cells promising candidates for cancer immunotherapy. In this study, we show that MAIT cells can be efficiently amplified in vitro, and these amplified MAIT cells are armed with potent anticancer functions, including the ability to produce significant amounts of effector molecules such as IFNγ and granzyme B. Excitingly, we demonstrate that MAIT cells can be redirected to potently kill cancerous cells using a clinically relevant bispecific monoclonal antibody. Furthermore, in an attempt to metabolically condition MAIT cells to improve function, we demonstrate that MAIT cells possess the molecular machinery to transport and metabolize lactate, an abundant metabolite within the solid tumor microenvironment. Activating MAIT cells in the presence of exogenous sodium lactate remodels their cellular metabolism, with a significant increase in mitochondrial metabolism. Functionally, this supports elevated production of effector molecules (IFNγ, granzymes A and B), leading to boosted engager mediated MAIT cell cytotoxicity. These data collectively show that MAIT cells can be pharmacologically directed to target cancer cells and in vitro conditioning using sodium lactate can enhance their anticancer capabilities through reprogrammed cellular metabolism. Our findings represent a novel strategy for a potential new adoptive cancer immunotherapy.