T cell branched glycosylation as a mediator of colitis-associated colorectal cancer progression: a potential new risk biomarker in Inflammatory Bowel Disease.

Abstract

Inflammatory Bowel Disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, established as a risk factor for Colorectal Cancer (CRC) development. Long-standing inflammation appears to play a central role in Colitis-associated Colorectal Cancer (CAC). However, the molecular mechanism underlying CAC progression is still elusive. Previous evidence showed that levels of branched glycosylation regulate T cell-mediated immune response associated with IBD severity. Here, we revealed that colonic T cells from IBD patients are dynamically regulated by branched N-glycosylation and associated with the risk of CAC development. The combined analysis of human IBD and CAC clinical samples, together with glycoengineered mouse model susceptible to CAC, revealed a gradual and dynamic increase of branched N-glycans in T cells from colitis to dysplasia and cancer. This glycosylation switch was shown to impose inhibitory properties in T cells, precluding an effective anti-tumor immune response. Mechanistically, we demonstrated that the deletion of branched N-glycans in Mgat5 KO mice led to CAC suppression due to increased infiltration of CD8+ and γδ T cells, contributing to an effective anti-tumor immune response. From the clinical standpoint, we demonstrated that branched N-glycosylation levels detected in inflamed lesions from IBD patients predicted CAC progression with a sensitivity of 83.3% and specificity of 67.9%, when assessed together with age at diagnosis. Overall, we here disclosed a new mechanism underlying CAC development, identifying a potential clinical biomarker plausible to improve the efficacy of cancer surveillance programs through the early identification of high risk IBD patients, for preventive clinical and therapeutic strategies.