Immune checkpoint regulation of the host-microbe interactome (360G-Wellcome-225875_Z_22_Z)

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.