Some cancer patients develop severe gut inflammation after treatment with immune checkpoint inhibitors, and this colitis is driven by the trillions of bacteria living in their intestines. This matters because immune checkpoint inhibitors are powerful cancer therapies, but the colitis they trigger can be debilitating and sometimes forces patients to stop treatment. Researchers do not yet understand exactly how gut bacteria and the immune system interact to cause this damage, so there is no targeted way to prevent or treat it without undermining the cancer therapy. The study will map the molecular conversations between specific immune cells, bacterial metabolites, and surrounding tissue in patients who develop colitis. If successful, it could reveal which bacterial by-products or immune signals trigger the inflammation, pointing toward new treatments that spare the cancer-fighting effects of the drugs. The work is primarily curiosity-driven fundamental science about how the immune system distinguishes friend from foe at barrier surfaces, but understanding this basic biology has already led to breakthroughs in autoimmune disease and transplant medicine.
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Immune checkpoint molecules (e.g. CTLA4, PD-1) restrain immune activation, especially at barrier surfaces where potent inflammatory cues are abundant, including trillions of commensal bacteria. This is exemplified by the microbiota-dependent colitis developing in cancer patients treated with immune checkpoint inhibitors (CPI). Mechanistically resolving the immunopathology of CPI-colitis affords a novel, experimental medicine opportunity to understand immune checkpoint regulation of the host-microbe interactome. Using longitudinally sampled mucosal biopsies from CPI-treated patients, and novel CPI-colitis models, I will test the hypothesis that microbially-derived metabolites induce IL27-responsive, polyfunctional CXCR6+ T-cells, which are responsible for mediating CPI-colitis. IL27 regulated transcriptional modules in colonic CXCR6+ T-cells will be mapped during transitions from health to disease using parallel scRNA-seq, scATAC seq and proteome profiling. Communication networks between CXCR6+ T-cells, IL27-expressing mononuclear phagocytes, and neighbouring cells will be spatio-temporally resolved using spatial transcriptomics. The CPI-colitis associated metabolome will be longitudinally defined in patients (NMR and LC-MS). The functional impact of disease-associated metabolites, IL27 and CXCR6+ lymphocyte effector pathways will be mechanistically probed in relevant preclinical models. Beyond informing much needed treatment strategies for patients with CPI-colitis, this study will provide novel insights into the fundamental biology of immunometabolic regulation of mucosal immune function.
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