谷歌Chrome浏览器插件
订阅小程序
在清言上使用

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

JOURNAL FOR IMMUNOTHERAPY OF CANCER(2024)

引用 0|浏览4
暂无评分
摘要
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-na & iuml;ve 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 alpha 4 beta 7 ligand molecular vascular addressin cell adhesion molecule 1 (MAdCAM-1), which may preferentially respond to vedolizumab (anti-alpha 4 beta 7). Conclusions These findings nominate CD4(+) RM and MAdCAM-1(+) endothelial cells for targeting in specific subsets of CPI colitis patients.
更多
查看译文
关键词
Immune related adverse event - irAE,Colitis,Memory,Immune Checkpoint Inhibitor
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要