{"doi":"10.1084/jem.20221333","title":"Intestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration","abstract":"Immune checkpoint blockade (ICB) has revolutionized cancer treatment, yet quality of life and continuation of therapy can be constrained by immune-related adverse events (irAEs). Limited understanding of irAE mechanisms hampers development of approaches to mitigate their damage. To address this, we examined whether mice gained sensitivity to anti-CTLA-4 (αCTLA-4)-mediated toxicity upon disruption of gut homeostatic immunity. We found αCTLA-4 drove increased inflammation and colonic tissue damage in mice with genetic predisposition to intestinal inflammation, acute gastrointestinal infection, transplantation with a dysbiotic fecal microbiome, or dextran sodium sulfate administration. We identified an immune signature of αCTLA-4-mediated irAEs, including colonic neutrophil accumulation and systemic interleukin-6 (IL-6) release. IL-6 blockade combined with antibiotic treatment reduced intestinal damage and improved αCTLA-4 therapeutic efficacy in inflammation-prone mice. Intestinal immune signatures were validated in biopsies from patients with ICB colitis. Our work provides new preclinical models of αCTLA-4 intestinal irAEs, mechanistic insights into irAE development, and potential approaches to enhance ICB efficacy while mitigating irAEs.","journal":"The Journal of Experimental Medicine","year":2022,"id":237017,"datarank":0.6261580904843456,"base_score":4.174387269895637,"endowment":4.174387269895637,"self_citation_contribution":0.6261580904843456,"citation_network_contribution":0.0,"self_endowment_contribution":0.6261580904843456,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":64,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9587,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":277291,"name":"Yusra B. Medik","orcid":"0000-0003-0763-3719","position":1,"is_corresponding":false},{"id":509604,"name":"Bhakti Patel","orcid":"0000-0002-8090-0193","position":2,"is_corresponding":false},{"id":271517,"name":"Daniel Zamler","orcid":"0000-0003-0375-8119","position":3,"is_corresponding":false},{"id":858610,"name":"Sijie Chen","orcid":"0000-0003-4331-0773","position":4,"is_corresponding":false},{"id":858611,"name":"Thomas Chapman","orcid":"0000-0002-5723-5498","position":5,"is_corresponding":false},{"id":689233,"name":"Sarah Schneider","orcid":"0000-0001-7027-7978","position":6,"is_corresponding":false},{"id":552280,"name":"Elizabeth M. Park","orcid":"0000-0002-1670-2299","position":7,"is_corresponding":false},{"id":277290,"name":"Rachel L. Babcock","orcid":"0000-0002-1848-5494","position":8,"is_corresponding":false},{"id":277288,"name":"Taylor T. Chrisikos","orcid":"0000-0001-8966-4046","position":9,"is_corresponding":false},{"id":574528,"name":"Laura M. Kahn","orcid":"0000-0002-6679-7599","position":10,"is_corresponding":false},{"id":515963,"name":"Allison M. Dyevoich","orcid":"0000-0002-4106-0435","position":11,"is_corresponding":false},{"id":858612,"name":"Josué E. Pineda","orcid":"0000-0002-8132-1804","position":12,"is_corresponding":false},{"id":550008,"name":"Matthew C. Wong","orcid":"0000-0002-6317-2526","position":13,"is_corresponding":false},{"id":858613,"name":"Aditya K. Mishra","orcid":"0000-0003-0775-3219","position":14,"is_corresponding":false},{"id":858614,"name":"Samuel Cass","orcid":"0000-0001-6160-2177","position":15,"is_corresponding":false},{"id":90425,"name":"Alexandria P. Cogdill","orcid":"0000-0001-8917-9462","position":16,"is_corresponding":false},{"id":839884,"name":"Daniel H. Johnson","orcid":"0000-0002-4778-686X","position":17,"is_corresponding":false},{"id":616278,"name":"Sarah B. Johnson","orcid":"0000-0001-8936-0958","position":18,"is_corresponding":false},{"id":320444,"name":"Khalida Wani","orcid":"0000-0002-2383-3908","position":19,"is_corresponding":false},{"id":858615,"name":"Debora Alejandra Ledesma","orcid":"0000-0002-6670-7645","position":20,"is_corresponding":false},{"id":90426,"name":"Courtney W. Hudgens","orcid":"0000-0001-8312-7485","position":21,"is_corresponding":false},{"id":295386,"name":"Jingjing Wang","orcid":"0000-0002-6211-6717","position":22,"is_corresponding":false},{"id":616370,"name":"M.A. Wadud Khan","orcid":"0000-0003-0596-862X","position":23,"is_corresponding":false},{"id":295093,"name":"Christine B. Peterson","orcid":"0000-0003-3316-0468","position":24,"is_corresponding":false},{"id":413961,"name":"Aron Y. Joon","orcid":"0000-0003-2615-2179","position":25,"is_corresponding":false},{"id":254697,"name":"Weiyi Peng","orcid":"0000-0002-7785-6240","position":26,"is_corresponding":false},{"id":277292,"name":"Haiyan S. Li","orcid":"0000-0001-5069-9735","position":27,"is_corresponding":false},{"id":104286,"name":"Reetakshi Arora","orcid":"0000-0002-5437-4521","position":28,"is_corresponding":false},{"id":261732,"name":"Ximing Tang","orcid":"0000-0001-6534-6852","position":29,"is_corresponding":false},{"id":311145,"name":"Maria Gabriela Raso","orcid":"0000-0003-2105-5556","position":30,"is_corresponding":false},{"id":66241,"name":"Xuegong Zhang","orcid":"0000-0002-9684-5643","position":31,"is_corresponding":false},{"id":332453,"name":"Wai Chin Foo","orcid":"0000-0002-0471-4911","position":32,"is_corresponding":false},{"id":90468,"name":"Michael T. Tetzlaff","orcid":"0000-0001-7899-4138","position":33,"is_corresponding":false},{"id":351341,"name":"Gretchen E. Diehl","orcid":"0000-0002-1841-2842","position":34,"is_corresponding":false},{"id":232776,"name":"Karen Clise-Dwyer","orcid":"0000-0001-9954-1197","position":35,"is_corresponding":false},{"id":236802,"name":"Elizabeth M. Whitley","orcid":"0000-0001-5737-5645","position":36,"is_corresponding":false},{"id":809136,"name":"Matthew M. Gubin","orcid":"0000-0001-7443-2752","position":37,"is_corresponding":false},{"id":90470,"name":"James P. Allison","orcid":"0000-0001-8980-5697","position":38,"is_corresponding":false},{"id":72142,"name":"Patrick Hwu","orcid":"0000-0002-8293-1313","position":39,"is_corresponding":false},{"id":90467,"name":"Nadim J. Ajami","orcid":"0000-0002-3808-8576","position":40,"is_corresponding":false},{"id":90456,"name":"Adi Diab","orcid":"0000-0002-0153-0244","position":41,"is_corresponding":false},{"id":72152,"name":"Jennifer A. Wargo","orcid":"0000-0003-3438-7576","position":42,"is_corresponding":false},{"id":277293,"name":"Stephanie S. Watowich","orcid":"0000-0003-1969-659X","position":43,"is_corresponding":false},{"id":277287,"name":"Yifan Zhou","orcid":"0000-0003-0975-1479","position":0,"is_corresponding":true}],"reference_count":73,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:22:08.925400Z","pmid":"36367776","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}