The microbial metabolite butyrate enhances the effector and memory functions of murine CD8+ T cells and improves anti-tumor activity

Abstract

Introduction: CD8+ T cells are vital in the immune control of cancer and a key player in cell-based cancer immunotherapy. Recent studies have shown that microbial short-chain fatty acids (SCFA) can promote both effector and memory phenotypes in CD8+ T cells and may thereby enhance protection against cancer. Methods: In this study, we determined the effect of SCFA butyrate on mouse CD8+ T cell function in vitro and in vivo, using the OT-I model. Results: Butyrate co-culture with anti-CD3 + anti-CD28 activated T cells in vitro enhanced the frequency of effector CD8+ IFN-γ-producing cells, and the amount of cytokine produced per cell. Culture with butyrate also enhanced the activation, TCR expression, and levels of phosphorylated mTOR proteins within CD8+ T cells but reduced proliferation rate and increased apoptosis. Butyrate-treated activated cells conferred tumor protection after adoptive transfer. Butyrate-treated cells were present at higher frequencies within the tumor compared to non-butyrate treated cells, and expressed IFN-γ. When analyzed using high dimensional cytometry, the tumors of mice that received butyrate-treated cells were enriched in clusters displaying an effector memory phenotype with high expression of IL-15Rβ and T-bet. Discussion: Our findings show that butyrate promotes the effector activity of CD8+ T cells in culture, which can persist in vivo while also stimulating memory phenotypes. Consequently, butyrate treatment may have strong application in T cell-based immunotherapies to improve protective cell functions and patient outcomes.