Dysregulated B cell Responses Are Associated with Immune Checkpoint Inhibitor-Induced Colitis Development and Severity 9101

Abstract Description The landscape of cancer therapy has been transformed by immune checkpoint inhibitors (ICIs), which reinvigorate T cell responses through the blockade of immune checkpoints such as PD-1 and CTLA-4. However, 40% of patients experience off-target inflammatory diseases known as immune related adverse events (irAEs). ICI-colitis is one of the most common and debilitating irAEs and often necessitates the use of immunosuppressive therapies, compromising anti-tumor immunity. Currently, treatment options for irAEs are limited due to a lack of mechanistic understanding caused by a deficit of robust preclinical models that mimic the human disease. Here, we have developed a murine model of ICI-colitis caused by latent intestinal epithelial injury and dysbiosis which only becomes symptomatic following ICI therapy. Through this model, we uncover a complex underlying mechanism of colitis-irAE which is associated with the altered function of B cells. Prior to symptom development, we observe altered B cell migration and functionality, which precedes hallmark type 1 and 17 T cell responses. Importantly, B cell depletion prior to but not after ICI administration impedes the development of ICI-colitis. Collectively, our data suggests that subclinical intestinal perturbations alter the functional status of B cells that will drive proinflammatory functionality in T cells following ICI use, which ultimately leads to the development of symptomatic colitis. Funding Sources This work was supported by NIH R01 grants (R.N.), Wilkes Melanoma Foundation grant (R.N.), NIH/NCI Melanoma and GI SPORE grants (R.N.), and Institutional Research Grant (IRG) (R.N.). Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)