Suppression of local IFN-I by commensal microbiota-derived butyrate impairs antitumor effects of ionizing radiation

Abstract

Abstract The antitumor effects of ionizing radiation (IR) are mediated in part through activation of innate and adaptive immunity. Here, we report that gut microbiota influences tumor control following IR. Vancomycin decreased the abundance of butyrate-producing gut bacteria, accompanied with reduction of butyric acid in circulation and tumor tissues, and enhanced antitumor responses to IR. Oral administration of Lachnospiraceae, a family of vancomycin-sensitive bacteria, associated with increased systemic and intratumoral butyric acid levels and impaired the efficacy of IR in germ-free (GF) mice. Local butyrate inhibited STING-activated type I IFN expression in dendritic cells (DCs) through blockade of TBK 1 and IRF3 phosphorylation, which abrogated IR-induced tumor-specific cytotoxic T cell immune responses without directly protecting tumor cells from radiation. Our findings demonstrate that the selective targeting of butyrate-producing microbiota may provide a novel therapeutic option to enhance tumor radiation sensitivity. This work was supported by a grant from the Ludwig Foundation to R.R. Weichselbaum, and National Institutes of Health/National Cancer Institute Provocative Questions grants R21 CA227528 and R21 CA231273-01 (R.R. Weichselbaum).