Abstract
<h3>Background and Aims</h3> 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. CPI-induced colitis is a common a serious complication. <h3>Methods</h3> To probe the impact of immune checkpoints on intestinal homeostasis mice were challenged with combination anti-CTLA4 and anti-PD-1 immunotherapy, manipulation of the intestinal microbiota and antibody blockade/depletion studies. Colonic immune responses were profiled using RNA-sequencing, including high-resolution single cell analyses, and flow cytometry. <h3>Results</h3> CPI-colitis was dependent on the composition of the intestinal microbiota and was characterized by remodelling of mucosal lymphocytes with induction of polyfunctional lymphocyte responses characterized by increased expression of interferon-γ (IFNγ), other pro-inflammatory cytokines/chemokines (<i>Il22</i>, <i>Il17a Ccl3, Ccl4</i> and <i>Ccl9</i>), cytotoxicity molecules (<i>Gzmb</i>, <i>Gzma</i>, <i>Prf1</i>, <i>Nkg7</i>) and the chemokine receptor <i>Cxcr6</i>. In comparison with mucosal lymphocytes in the steady state, polyfunctional lymphocytes from both CD4<sup>+</sup> and CD8<sup>+</sup> lineages upregulated costimulatory molecules and checkpoint molecules in CPI-colitis, indicating that these cells are tightly regulated. CPI-colitis was attenuated following depletion of effector lymphocytes or following blockade of the IL23/IFNγ axis. <h3>Conclusions</h3> This study provides new mechanistic insights into CPI-colitis, identifying polyfunctional, cytotoxic lymphocytes as key mediators of disease. Therapeutic targeting of their effector response or regulatory networks, including the IL23/IFNγ axis holds the key to preventing and reversing CPI-colitis.
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