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.
- 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.
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.