| Autor: |
Li Zhang, Lawrence Fong, Brittany Davidson, David Y Oh, Frances Fan, Alexander Cheung, Hai Yang, Jun Yan He, Yang-Joon Kim, Elvira Mennillo, Iulia Rusu, Jared Bain, Arjun A Rao, Christopher Andersen, Karen Law, Jessica Tsui, Alan Shen, Divyashree Kushnoor, Yimin Shi, Alexis J Combes, Angela O Pisco, Michael G Kattah |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
|
| Zdroj: |
Journal for ImmunoTherapy of Cancer, Vol 12, Iss 4 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2051-1426 |
| DOI: |
10.1136/jitc-2023-008628 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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