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
  • 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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