TIGHT JUNCTION PLAYS AN ESSENTIAL ROLE IN IMMUNOTHERAPY-INDUCED COLITIS AND TUMOR PROGRESSION

Immune checkpoint inhibitors (ICIs), such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed cell death protein 1 (PD-1), have revolutionized cancer treatment and survival. However, ICIs can lead to immune-related adverse events, notably colitis. Our prior work highlighted the essential role of myosin light chain kinase (MLCK) dependent tight junction permeability increases as a driver of inflammatory bowel disease. Here, we aim to explore the tight junction related gut barrier's function in ICIs colitis and find ways to adjuvant therapy for tumors. Initially, staining in human samples with colitis induced by anti-PD1 antibodies revealed reduced expression of tight junction proteins ZO-1 and occludin and increased MLCK expression. Analysis of a novel mouse model of anti-CTLA4 and anti-PD-1-induced ICI colitis led to reduced ZO-1 and occludin expression and increased MLCK expression. Implanation of melanoma tumor cells (without ICIs) led to intestinal barrier loss.Combined ICI antibody therapy effectively limited progression of early-stage tumors and improved gut barrier function, potentially due to tumor growth blockage. To assess tumorigenesis, we employed the AOM-DSS model of colitis-associated colorectal cancer, treated it with antibodies for 8 weeks, the results showed that long term treatment with ICIs induced intestinal barrier loss. Finally, tacrolimus, a calcineurin inhibitor that inhibits MLCK recruitment to tight junctions and reverses inflammation-induced barrier loss, enhanced intestinal barrier function and improved tumor immunotherapy effectiveness. These data suggest that MLCK-dependent tight junction regulation impacts ICI efficacy and tumorigenesis and that barrier restoration may provide an approach to ICI colitis therapy.