{"doi":"10.1136/jitc-2023-007736","title":"Polycomb repressor complex 2 suppresses interferon-responsive MHC-II expression in melanoma cells and is associated with anti-PD-1 resistance","abstract":"BACKGROUND: Despite the remarkable success of immunotherapy in treating melanoma, understanding of the underlying mechanisms of resistance remains limited. Emerging evidence suggests that upregulation of tumor-specific major histocompatibility complex-II (tsMHC-II) serves as a predictive marker for the response to anti-programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) therapy in various cancer types. The genetic and epigenetic pathways modulating tsMHC-II expression remain incompletely characterized. Here, we provide evidence that polycomb repressive complex 2 (PRC2)/EZH2 signaling and resulting H3K27 hypermethylation suppresses tsMHC-II. METHODS: RNA sequencing data from tumor biopsies from patients with cutaneous melanoma treated with or without anti-PD-1, targeted inhibition assays, and assays for transposase-accessible chromatin with sequencing were used to observe the relationship between EZH2 inhibition and interferon (IFN)-γ inducibility within the MHC-II pathway. RESULTS: We find that increased EZH2 pathway messenger RNA (mRNA) expression correlates with reduced mRNA expression of both presentation and T-cell genes. Notably, targeted inhibition assays revealed that inhibition of EZH2 influences the expression dynamics and inducibility of the MHC-II pathway following IFN-γ stimulation. Additionally, our analysis of patients with metastatic melanoma revealed a significant inverse association between PRC2-related gene expression and response to anti-PD-1 therapy. CONCLUSIONS: , the master regulator of MHC-II. These insights shed light on the molecular mechanisms involved in tsMHC-II suppression and highlight the potential of targeting EZH2 as a therapeutic strategy to improve immunotherapy efficacy.","journal":"Journal for ImmunoTherapy of Cancer","year":2023,"id":326355,"datarank":0.5101796072493234,"base_score":3.4011973816621555,"endowment":3.4011973816621555,"self_citation_contribution":0.5101796072493234,"citation_network_contribution":0.0,"self_endowment_contribution":0.5101796072493234,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":29,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9618,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":840046,"name":"Brandie C. Taylor","orcid":"0000-0002-4862-4678","position":1,"is_corresponding":false},{"id":236798,"name":"Margaret L. Axelrod","orcid":"0000-0003-4713-8798","position":2,"is_corresponding":false},{"id":640396,"name":"Xiaopeng Sun","orcid":"0009-0009-5219-8964","position":3,"is_corresponding":false},{"id":849726,"name":"Lindsey N. Guerin","orcid":"0000-0002-2070-4481","position":4,"is_corresponding":false},{"id":245504,"name":"Paula I. González-Ericsson","orcid":"0000-0002-6292-6963","position":5,"is_corresponding":false},{"id":832161,"name":"Yu Wang","orcid":"0000-0002-2819-4551","position":6,"is_corresponding":false},{"id":321041,"name":"Violeta Sánchez","orcid":"0000-0001-6639-9024","position":7,"is_corresponding":false},{"id":599891,"name":"Catherine C. Fahey","orcid":"0000-0003-4347-361X","position":8,"is_corresponding":false},{"id":34060,"name":"Melinda E. Sanders","orcid":"0000-0001-7227-1764","position":9,"is_corresponding":false},{"id":432431,"name":"Yaomin Xu","orcid":"0000-0002-3752-4006","position":10,"is_corresponding":false},{"id":17369,"name":"Emily Hodges","orcid":"0000-0001-6513-610X","position":11,"is_corresponding":false},{"id":28327,"name":"Douglas B. Johnson","orcid":"0000-0002-6390-773X","position":12,"is_corresponding":false},{"id":236816,"name":"Justin M. Balko","orcid":"0000-0002-4263-5974","position":13,"is_corresponding":false},{"id":253119,"name":"Jamaal L. James","orcid":null,"position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:08:33.106703Z","pmid":"38315170","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":[]}