e-Article
Dysregulation of CD4+ and CD8+ resident memory T, myeloid, and stromal cells in steroid-experienced, checkpoint inhibitor colitis.
Document Type
article
Author
He, Jun; Kim, Yang-Joon; Mennillo, Elvira; Rusu, Iulia; Bain, Jared; Rao, Arjun; Andersen, Christopher; Law, Karen; Yang, Hai; Tsui, Jessica; Shen, Alan; Davidson, Brittany; Kushnoor, Divyashree; Shi, Yimin; Fan, Frances; Cheung, Alexander; Zhang, Li; Fong, Lawrence; Combes, Alexis; Pisco, Angela; Oh, David; Kattah, Michael
Source
Journal for ImmunoTherapy of Cancer. 12(4)
Subject
Language
Abstract
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 CD4+resident 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.