{"doi":"10.1172/jci191781","title":"Loss of tumor cell MHC class II drives MAPK inhibitor insensitivity of BRAF-mutant anaplastic thyroid cancers","abstract":"Cancer cells present neoantigens dominantly through MHC class I (MHCI) to drive tumor rejection through cytotoxic CD8+ T cells. There is growing recognition that a subset of tumors express MHC class II (MHCII), causing recognition of antigens by TCRs of CD4+ T cells that contribute to the antitumor response. We found that mouse BrafV600E-driven anaplastic thyroid cancers (ATCs) responded markedly to the RAF plus MEK inhibitors dabrafenib and trametinib (dab/tram) and that this was associated with upregulation of MhcII in cancer cells and increased CD4+ T cell infiltration. A subset of recurrent tumors lost MhcII expression due to silencing of Ciita, the master transcriptional regulator of MhcII, despite preserved IFN-γ signal transduction, which could be rescued by EZH2 inhibition. Orthotopically implanted Ciita-/- and H2-Ab1-/- ATC cells into immune-competent mice became unresponsive to the MAPK inhibitors. Moreover, depletion of CD4+, but not CD8+, T cells also abrogated the response to dab/tram. These findings implicate MHCII-driven CD4+ T cell activation as a key determinant of the response of Braf-mutant ATCs to MAPK inhibition.","journal":"Journal of Clinical Investigation","year":2025,"id":572735,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9392,"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":1455298,"name":"Jillian Greenberg","orcid":null,"position":1,"is_corresponding":false},{"id":1203088,"name":"Tianyue Qin","orcid":"0000-0002-4656-7470","position":2,"is_corresponding":false},{"id":1455299,"name":"Soo-Yeon Im","orcid":null,"position":3,"is_corresponding":false},{"id":277158,"name":"Gnana P. Krishnamoorthy","orcid":"0000-0002-6139-5435","position":4,"is_corresponding":false},{"id":108811,"name":"Laura Boucai","orcid":"0000-0002-8852-1120","position":5,"is_corresponding":false},{"id":250488,"name":"Bin Xu","orcid":"0000-0003-4638-9835","position":6,"is_corresponding":false},{"id":1404408,"name":"Jena D. French","orcid":"0000-0002-8881-6543","position":7,"is_corresponding":false},{"id":255786,"name":"Eric J. Sherman","orcid":"0000-0002-4960-4783","position":8,"is_corresponding":false},{"id":235764,"name":"Alan L. Ho","orcid":"0000-0002-6885-3742","position":9,"is_corresponding":false},{"id":225995,"name":"Elisa de Stanchina","orcid":"0000-0002-3873-315X","position":10,"is_corresponding":false},{"id":14071,"name":"Nicholas D. Socci","orcid":"0000-0002-8254-6925","position":11,"is_corresponding":false},{"id":228877,"name":"Jian Jin","orcid":"0000-0002-2387-3862","position":12,"is_corresponding":false},{"id":15538,"name":"Ronald A. Ghossein","orcid":null,"position":13,"is_corresponding":false},{"id":277160,"name":"Jeffrey A. Knauf","orcid":"0000-0003-4456-8792","position":14,"is_corresponding":false},{"id":240165,"name":"Richard P. Koche","orcid":"0000-0002-6820-5083","position":15,"is_corresponding":false},{"id":108810,"name":"James A. Fagin","orcid":"0000-0002-2365-2517","position":16,"is_corresponding":false},{"id":277159,"name":"Vera Tiedje","orcid":"0000-0003-3612-0779","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:57:27.876396Z","pmid":"40828595","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":[]}