{"doi":"10.1172/jci153437","title":"Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert microenvironment and is sensitized by immunogenic viruses","abstract":"Immune checkpoint blockade (ICB) has demonstrated clinical success in \"inflamed\" tumors with substantial T cell infiltrates, but tumors with an immune-desert tumor microenvironment (TME) fail to benefit. The tumor cell-intrinsic molecular mechanisms of the immune-desert phenotype remain poorly understood. Here, we demonstrated that inactivation of the polycomb-repressive complex 2 (PRC2) core components embryonic ectoderm development (EED) or suppressor of zeste 12 homolog (SUZ12), a prevalent genetic event in malignant peripheral nerve sheath tumors (MPNSTs) and sporadically in other cancers, drove a context-dependent immune-desert TME. PRC2 inactivation reprogramed the chromatin landscape that led to a cell-autonomous shift from primed baseline signaling-dependent cellular responses (e.g., IFN-γ signaling) to PRC2-regulated developmental and cellular differentiation transcriptional programs. Further, PRC2 inactivation led to diminished tumor immune infiltrates through reduced chemokine production and impaired antigen presentation and T cell priming, resulting in primary resistance to ICB. Intratumoral delivery of inactivated modified vaccinia virus Ankara (MVA) enhanced tumor immune infiltrates and sensitized PRC2-loss tumors to ICB. Our results identify molecular mechanisms of PRC2 inactivation-mediated, context-dependent epigenetic reprogramming that underline the immune-desert phenotype in cancer. Our studies also point to intratumoral delivery of immunogenic viruses as an initial therapeutic strategy to modulate the immune-desert TME and capitalize on the clinical benefit of ICB.","journal":"Journal of Clinical Investigation","year":2022,"id":250647,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9597,"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":892859,"name":"Yuedan Chen","orcid":"0000-0001-5665-268X","position":1,"is_corresponding":false},{"id":885500,"name":"Amish J. Patel","orcid":"0000-0002-4214-2619","position":2,"is_corresponding":false},{"id":885501,"name":"Sarah Warda","orcid":"0000-0001-8067-8804","position":3,"is_corresponding":false},{"id":885504,"name":"Cindy J. Lee","orcid":"0000-0002-2613-4387","position":4,"is_corresponding":false},{"id":240583,"name":"Briana G. Nixon","orcid":"0000-0001-7334-9404","position":5,"is_corresponding":false},{"id":885509,"name":"Elissa W.P. Wong","orcid":"0000-0003-4843-9816","position":6,"is_corresponding":false},{"id":842742,"name":"Miguel A. Miranda-Román","orcid":"0000-0003-4914-848X","position":7,"is_corresponding":false},{"id":573542,"name":"Ning Yang","orcid":"0000-0001-5121-7208","position":8,"is_corresponding":false},{"id":306852,"name":"Yi Wang","orcid":"0000-0003-4060-5736","position":9,"is_corresponding":false},{"id":885503,"name":"Mohini R. Pachai","orcid":"0000-0003-1143-0607","position":10,"is_corresponding":false},{"id":893485,"name":"Jessica Sher","orcid":null,"position":11,"is_corresponding":false},{"id":885511,"name":"Emily Giff","orcid":"0000-0003-0665-8738","position":12,"is_corresponding":false},{"id":294384,"name":"Fanying Tang","orcid":"0000-0003-1887-5764","position":13,"is_corresponding":false},{"id":13116,"name":"Ekta Khurana","orcid":"0000-0002-4351-7566","position":14,"is_corresponding":false},{"id":64014,"name":"S. J. Singer","orcid":null,"position":15,"is_corresponding":false},{"id":545496,"name":"Yang Liu","orcid":"0000-0002-5804-0043","position":16,"is_corresponding":false},{"id":584348,"name":"Phillip M. Galbo","orcid":"0000-0002-5391-598X","position":17,"is_corresponding":false},{"id":262960,"name":"Jesper L.V. Mååg","orcid":"0000-0002-2578-8872","position":18,"is_corresponding":false},{"id":240165,"name":"Richard P. Koche","orcid":"0000-0002-6820-5083","position":19,"is_corresponding":false},{"id":284103,"name":"Deyou Zheng","orcid":"0000-0003-4354-5337","position":20,"is_corresponding":false},{"id":35289,"name":"Cristina R. Antonescu","orcid":"0000-0002-9717-8205","position":21,"is_corresponding":false},{"id":573544,"name":"Liang Deng","orcid":"0000-0002-8467-9342","position":22,"is_corresponding":false},{"id":240589,"name":"Ming O. Li","orcid":"0000-0002-1383-0535","position":23,"is_corresponding":false},{"id":259330,"name":"Yu Chen","orcid":"0000-0002-0171-3884","position":24,"is_corresponding":false},{"id":245664,"name":"Ping Chi","orcid":"0000-0002-0159-5531","position":25,"is_corresponding":false},{"id":885510,"name":"Juan Yan","orcid":"0000-0001-7130-945X","position":0,"is_corresponding":true}],"reference_count":81,"raw_metadata":null,"created_at":"2026-07-19T00:24:32.960657Z","pmid":"35852856","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":[]}