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

Authors
  • 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
  • And 2 more
Publication Date
Apr 19, 2024
Source
eScholarship - University of California
Keywords
License
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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.

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