{"doi":"10.1136/jitc-2023-008628","title":"Dysregulation of CD4<sup>+</sup>and CD8<sup>+</sup>resident memory T, myeloid, and stromal cells in steroid-experienced, checkpoint inhibitor colitis","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.","journal":"Journal for ImmunoTherapy of Cancer","year":2024,"id":427306,"datarank":0.5068064071913649,"base_score":2.772588722239781,"endowment":2.772588722239781,"self_citation_contribution":0.41588830833596724,"citation_network_contribution":0.0909180988553977,"self_endowment_contribution":0.41588830833596724,"citer_contribution":0.0909180988553977,"corpus_percentile":null,"corpus_rank":null,"citation_count":15,"citer_count":13,"citers_with_citation_signal":5,"citers_with_endowment":5,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9481,"is_data_producer":true,"deposit_databanks":{"figshare":["10.6084/m9.figshare.2466892","10.6084/m9.figshare.24668916","10.6084/m9.figshare.24668925","10.6084/m9.figshare.24668934"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1227981,"name":"Yang-Joon Kim","orcid":null,"position":1,"is_corresponding":false},{"id":380203,"name":"Elvira Mennillo","orcid":"0000-0002-3210-1004","position":2,"is_corresponding":false},{"id":832016,"name":"I Rusu","orcid":"0000-0002-7146-0499","position":3,"is_corresponding":false},{"id":832552,"name":"Jared L. 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