The skin microbiota drives cutaneous immune checkpoint inhibitor toxicity in genetically susceptible mice.

Abstract

Immune checkpoint inhibitors (ICIs) show increasing promise for cancer therapy. However, patients can experience adverse events, particularly those with pre-existing autoimmune disease. We determined that the microbiome can drive ICI-induced systemic toxicity in a mouse model of autoimmune susceptibility. Specifically, ICI treatment of specific pathogen-free (SPF) Act1mice, which develop spontaneous autoimmunity due to a deficiency in an immune adaptor, resulted in systemic adverse events that were ameliorated by topical antibiotics. Moreover, germ-free (GF) Act1mice failed to develop ICI toxicity. Transfer of gut or skin microbiota from SPF Act1mice to GF Act1mice showed that only the skin microbiota rendered exGF mice sensitive to ICI toxicity. Notably, therapeutic application of topical antibiotics decoupled ICI-induced toxicity from anti-tumor efficacy in SPF Act1mice. This model provides a paradigm for future translational studies in cancer patients to mitigate adverse effects of ICIs and maximize their efficacy by targeting skin microbes.