Checkpoint Inhibitor Induced Colitis is Dependent on the Microbiota and Activation of Cytotoxic Innate and Adaptive Lymphocytes

Immune checkpoint inhibitors (CPI) have revolutionised cancer treatment, with previously untreatable disease now amenable to potential cure. Combination regimens of anti-CTLA4 and anti-PD-1 show enhanced efficacy but are prone to off target immune-mediated tissue injury, particularly at the barrier surfaces. We show that CPI-induced colitis is dependent on the composition of the intestinal microbiota and involves innate immune mechanisms. Single cell RNA sequencing identified remodelling of mucosal lymphocytes in CPI-induced colitis, including the emergence of polyfunctional, cytolytic responses in CD4+ T-cells and innate lymphoid cells (ILCs). Unexpectedly, colitis deteriorated following CD4+ T-cell depletion and was maintained in mice lacking adaptive immunity. We show that both human and mouse colonic ILCs express CTLA4, which is regulated by microbial and inflammatory cues, and is functionally important in restraining innate immune activation. We provide new mechanistic insights into immune regulation at the mucosal barrier and important implications for the treatment of CPI-induced autoimmunity.