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

Jun Yan He; Yang-Joon Kim; Elvira Mennillo; Iulia Rusu; Jared Bain; Arjun A Rao; Christopher Andersen; Karen Law; Hai Yang; Jessica Tsui; Alan Shen; Brittany Davidson; Divyashree Kushnoor; Yimin Shi; Frances Fan; Alexander Cheung; Li Zhang; Lawrence Fong; Alexis J Combes; Angela O Pisco; Michael G Kattah; David Y Oh

doi:10.1136/jitc-2023-008628

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.

Authors

Jun Yan He¹, Yang-Joon Kim², Elvira Mennillo³, Iulia Rusu³, Jared Bain³, Arjun A Rao⁴, Christopher Andersen⁴, Karen Law¹, Hai Yang¹, Jessica Tsui⁴, Alan Shen⁴, Brittany Davidson⁴, Divyashree Kushnoor⁴, Yimin Shi¹, Frances Fan¹, Alexander Cheung¹, Li Zhang¹, Lawrence Fong¹, Alexis J Combes^{3

4

5

6}, Angela O Pisco², 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 David.Oh@ucsf.edu michael.kattah@ucsf.edu.
⁸ Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, California, USA David.Oh@ucsf.edu michael.kattah@ucsf.edu.

^# Contributed equally.

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.

MeSH terms

CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes*
Colitis* / chemically induced
Colitis* / drug therapy
Endothelial Cells
Humans
Steroids / pharmacology
Steroids / therapeutic use
Stromal Cells
Tumor Necrosis Factor Inhibitors

Substances

Tumor Necrosis Factor Inhibitors
Steroids

Abstract

MeSH terms

Substances

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