Dysregulation of CD4 and CD8 resident memory T, myeloid, and stromal cells in steroid-experienced, checkpoint inhibitor colitis.

Background: Colitis caused by checkpoint inhibitors (CPI) is frequent and is treated with empiric steroids, but CPI colitis mechanisms in steroid-experienced or refractory disease are unclear.

Methods: Using colon biopsies and blood from predominantly steroid-experienced CPI colitis patients, we performed multiplexed single-cell transcriptomics and proteomics to nominate contributing populations.

Results: CPI colitis biopsies showed enrichment of CD4resident memory (RM) T cells in addition to CD8 RM and cytotoxic CD8 T cells. Matching T cell receptor (TCR) clonotypes suggested that both RMs are progenitors that yield cytotoxic effectors. Activated, CD38 HLA-DR CD4 RM and cytotoxic CD8 T cells were enriched in steroid-experienced and a validation data set of steroid-naïve CPI colitis, underscoring their pathogenic potential across steroid exposure. Distinct from ulcerative colitis, CPI colitis exhibited perturbed stromal metabolism (NAD, tryptophan) impacting epithelial survival and inflammation. Endothelial cells in CPI colitis after anti-TNF and anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) upregulated the integrin α4β7 ligand molecular vascular addressin cell adhesion molecule 1 (MAdCAM-1), which may preferentially respond to vedolizumab (anti-α4β7).

Conclusions: These findings nominate CD4 RM and MAdCAM-1 endothelial cells for targeting in specific subsets of CPI colitis patients.