W128 - Investigating the Mechanisms Underlying Regulatory T Cell Dysfunction in Ici-induced Colitis

Abstract Text: While immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, nearly 85% of patients experience autoimmune-like side effects known as immune-related adverse events (irAEs), with ICI-colitis being one of the most common. The mechanisms underlying irAEs remain poorly understood, particularly regarding the role of regulatory T cells (Tregs). Tregs are a subset of CD4 T cells essential for maintaining immune tolerance and preventing autoimmunity.
Recent findings from my work and others show a significant accumulation of proliferative, cytotoxic T cells in the colon. This is accompanied by upregulation of various type II interferon-associated genes. Specifically, Tregs exhibit increased expression of IL12RB2, CXCR3, and TBX21, suggesting that ICI-colitis is driven by Th1 responses. This distinguishes it from other colitis types, which are typically Th17-driven. Despite their activated phenotype and proliferation, Tregs are unable to control the autoimmunity occurring in the colon. We hypothesize that Treg suppression is dysfunctional in ICI-colitis.
To dissect the transcriptomic changes occurring in Tregs in the context of ICI-colitis, we will employ single-cell RNA sequencing, along with in vitro studies. These will shed light on the origin, stability, and effect of Th1-programs on Tregs. Additionally, we will use spatial transcriptomics to examine Treg/CD8 T cell interactions in the colon. This will allow us to assess the colocalization of CD8 T cells and Tregs, determine whether suppression is occurring, and if CD8 T cells exhibit resistance to Treg-mediated suppression upon ICI treatment. Collectively, these studies will provide crucial insights into the mechanisms underlying ICI-colitis and other irAEs.