P001 Immune checkpoint inhibitor-induced colitis is mediated by polyfunctional lymphocytes and is dependent on the IL23/IFNg axis

Abstract Background 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 off target immune-mediated tissue injury, particularly at the barrier surfaces. CPI-induced colitis is a common serious complication. Methods To probe impact immune checkpoints on intestinal homeostasis mice were challenged combination immunotherapy, manipulation microbiota antibody blockade/depletion studies. Colonic responses profiled using RNA-sequencing, including high-resolution single cell analyses, flow cytometry. Results CPI was dependent composition characterized by remodelling mucosal lymphocytes induction polyfunctional lymphocyte expression interferon-g (IFNg), other pro-inflammatory cytokines/chemokines (Il22, Il17a Ccl3, Ccl4 Ccl9) cytotoxicity molecules (Gzmb, Gzma, Prf1, Nkg7). In comparison in steady state, from both CD4+ CD8+ lineages upregulated costimulatory CPI-colitis, indicating that these cells usually very tightly regulated. CPI-colitis attenuated following depletion effector or blockade IL23/IFNg axis. Conclusion This study provides new mechanistic insights into identifying polyfunctional, cytotoxic as key mediators disease. Therapeutic targeting their response regulatory networks, axis holds preventing reversing CPI-colitis.