C57BL/6 mice cohoused with pet shop mice phenocopy immune-related adverse events associated with checkpoint inhibition

Abstract

Abstract Checkpoint inhibition has been successful in the treatment of a number of malignancies. These medications block inhibitory pathways in T cells and allow for their improved function in anti-tumor immune responses. An important factor limiting checkpoint inhibitor therapy is immune-related adverse events (irAE), which can involve any organ system. It is currently not possible to predict which patients will develop irAE or which tissues will be affected. Our understanding of the cellular and molecular factors driving irAE development remains limited, as immune sufficient specific pathogen free (SPF) C57BL/6 mice do not develop irAE when treated with checkpoint inhibition. We have previously reported that C57BL/6 mice cohoused with pet shop mice recapitulate aspects of the human adult immune system, while SPF C57BL/6 mice have immune systems resembling that of human neonates. We hypothesized that checkpoint inhibition in C57BL/6 mice cohoused with pet shop mice will phenocopy irAE development in humans. Here, we report that treating “dirty” C57BL/6 mice with anti-CTLA4 and anti-PD-L1 resulted in the development of irAE, including nephritis, dermatitis, and hepatitis, as evaluated by histology and serum lab values. Ongoing experiments include depletion of CD4 and CD8 T cells to determine whether irAE are mediated by these cells. To our knowledge, this represents the first model of irAE in immune sufficient C57BL/6 mice, enabling further investigation into the mechanistic understanding of irAE and development of treatments targeting irAE while leaving anti-tumor responses intact. DIABETES T32 RESEARCH TRAINING PROGRAM