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

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

  • J Immunother Cancer. 2024 Apr 19;12(4):e008628. doi: 10.1136/jitc-2023-008628.
Jun Yan He 1,  Yang-Joon Kim 2,  Elvira Mennillo 3,  Iulia Rusu 3,  Jared Bain 3,  Arjun A Rao 4,  Christopher Andersen 4,  Karen Law 1,  Hai Yang 1,  Jessica Tsui 4,  Alan Shen 4,  Brittany Davidson 4,  Divyashree Kushnoor 4,  Yimin Shi 1,  Frances Fan 1,  Alexander Cheung 1,  Li Zhang 1,  Lawrence Fong 1,  Alexis J Combes 3 4 5 6,  Angela O Pisco 2,  Michael G Kattah # 7,  David Y Oh # 8
Affiliations

Affiliations

  • 1 Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
  • 2 Chan Zuckerberg Biohub, San Francisco, California, USA.
  • 3 Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
  • 4 CoLabs, University of California, San Francisco, San Francisco, California, USA.
  • 5 Department of Pathology, University of California, San Francisco, San Francisco, California, USA.
  • 6 ImmunoX Initiative, University of California, San Francisco, San Francisco, California, USA.
  • 7 Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA [email protected] [email protected].
  • 8 Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, California, USA [email protected] [email protected].
  • # Contributed equally.
PMID: 38642938 DOI: 10.1136/jitc-2023-008628
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.

Keywords

Colitis; Immune Checkpoint Inhibitor; Immune related adverse event - irAE; Memory.

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