Immune checkpoint inhibitor-induced colitis

Immune checkpoint inhibitors (CPIs) have revolutionised cancer treatment, with previously untreatable disease now amenable to potential cure. Combination regimens of anti-CTLA-4 and anti-PD-1 show enhanced efficacy but are prone to off-target immune-mediated tissue injury, particularly at the barrier surfaces. To probe the impact of immune checkpoints on intestinal homeostasis, mice were challenged with anti-CTLA-4 and anti-PD-1 immunotherapy and manipulation of the intestinal microbiota. Colonic immune responses were profiled using bulk RNA sequencing, single-cell RNA sequencing and flow cytometry. CPI-colitis was dependent on the composition of the intestinal microbiota and was characterized by induction of lymphocytes expressing interferon-gamma (IFNgamma), cytotoxicity molecules and other pro-inflammatory cytokines/chemokines. CPI-colitis was attenuated following blockade of the IL23/IFNgamma axis. Therapeutic targeting of IFNgamma-producing lymphocytes or regulatory networks, may hold the key to reversing CPI-colitis.