Beneficial Effect of Antibiotics and Microbial Metabolites on Expanded Vδ2Vγ9 T Cells in Hepatocellular Carcinoma Immunotherapy

Animal experiments and clinical trials have shown that the gut microbiota modulates host immunity and immune checkpoint-mediated responses to tumor cells. However, it remains unclear whether microbiota can also play a role in the tumor immune response of gamma delta T cells, a kind of cell that targets cancer directly. Here, we report that microbiota dysbiosis induced by antibiotics enhanced gamma delta T cell efficacy during tumor therapy in a mouse model. Further microbiota and metabolite analysis revealed that the alteration of gamma delta T cell cytotoxicity might be closely associated with specific metabolites, which are produced by intestinal bacteria and stimulate gamma delta T cells to release more cytotoxic cytokines, such as granzyme B and perforin. Among the metabolites that we analyzed, 3-indopropionic acid (IPA) showed the highest concentration in antibiotic-treated mice and can improve the cytotoxic ability of gamma delta T cells bothin vitroandin vivo. Our research determined how the gut microbiota can influence the antitumor ability of gamma delta T cells and identified potential intermediate molecules that connect the gut microbiota and gamma delta T cells.