{"doi":"10.1172/jci.insight.198203","title":"Pretreatment naive T cells are associated with severe irAE following PD-1/CTLA-4 checkpoint blockade for melanoma","abstract":"Immune checkpoint inhibitors (ICIs) such as anti-PD-1 and anti-CTLA-4 antibodies are used to induce an immune response against many types of tumors. However, ICIs often also induce autoimmune responses, referred to as immune-related adverse events (irAEs), which occur unpredictably and at varying levels of severity. We utilized high-dimensional immunophenotyping of longitudinal blood samples from patients with metastatic melanoma treated with combination anti-PD-1/CTLA-4 therapy in a clinical trial to characterize alterations in immune profiles induced by combination ICI therapy and to identify immune features associated with severe irAE development. T cell profiling highlighted that ICI therapy induces prominent expansions of activated, CD38hi CD4+ and CD8+ T cells, which are frequently bound by the therapeutic anti-PD-1 antibody, as well as substantial changes in Treg phenotypes. However, neither the baseline frequency nor the extent of expansion of these cell populations was associated with severe irAE development. Rather, naive CD4+ T cell abundance pretreatment was significantly associated with development of severe irAEs and with the number of irAEs developed. These results indicate the abundance of naive CD4+ T cells as a predictive feature for the development of severe irAEs following combination ICI therapy.","journal":"JCI Insight","year":2025,"id":535554,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9563,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1149105,"name":"Alice Horisberger","orcid":"0000-0002-3732-8662","position":1,"is_corresponding":false},{"id":1149595,"name":"Mehreen Elahee","orcid":null,"position":2,"is_corresponding":false},{"id":1419635,"name":"I. Adejoorin","orcid":null,"position":3,"is_corresponding":false},{"id":520560,"name":"Nilasha Ghosh","orcid":"0000-0002-8799-9309","position":4,"is_corresponding":false},{"id":68931,"name":"Michael A. Postow","orcid":"0000-0002-3367-7961","position":5,"is_corresponding":false},{"id":226219,"name":"Laura T. Donlin","orcid":"0000-0002-1428-090X","position":6,"is_corresponding":false},{"id":520563,"name":"Anne R. Bass","orcid":"0000-0002-3225-8351","position":7,"is_corresponding":false},{"id":226249,"name":"Deepak A. Rao","orcid":"0000-0001-9672-7746","position":8,"is_corresponding":false},{"id":669655,"name":"Kathryne E. Marks","orcid":"0000-0002-1524-7159","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:51:56.297114Z","pmid":"41296821","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":[]}