Microbiota-dependent model of immune checkpoint inhibitor colitis characterized by inflammatory immune cells and altered hematopoiesis 9088

Abstract Description While immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, many patients treated with ICI develop immune-related adverse events (irAEs) such as colitis. The exact etiology of ICI colitis remains unknown, but growing evidence indicates that gut microbiome composition impacts colitis development. Given that host response to microbiota is mediated by intestinal immunity, we hypothesized that inflammatory signaling by colonic immune cells drives ICI colitis. Thus, we developed a murine model of colitis dependent on both the gut microbiome and ICI, sensitizing otherwise healthy mice to ICI colitis. We ablated the endogenous gut microbiome of wild type mice using broad spectrum antibiotics before colonizing the gut with a dysbiotic microbiome via fecal microbiota transplant (FMT). B16F10-OVA tumors were then implanted and mice were treated with αCTLA-4. Our results show that mice given FMT and αCTLA-4, but not FMT or ICI alone, develop histological colitis. The colon lamina propria contains greater numbers of Th1 cells, neutrophils, monocytes, and DCs, as well as higher IL-6, IFNγ, and CTLA-4 expression in specific immune subsets. Bone marrow analysis in mice with ICI colitis shows myelopoiesis and increased numbers of lymphoid progenitors. Finally, tumors are less responsive to αCTLA-4 in mice with dysbiotic microbiota. Our work provides a preclinical model of ICI colitis that enables further evaluation of disease etiology and approaches to suppress this irAE. Funding Sources Supported by the Vivian L. Smith Endowment. SMS is a Graduate Scholar in the CPRIT Training Program (RP 210028). Topic Categories Mucosal and Regional Immunology (MUC)