{"doi":"10.1101/2025.01.27.635086","title":"Loss of tumor cell MHC Class II drives insensitivity of BRAF-mutant anaplastic thyroid cancers to MAPK inhibitors","abstract":"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 anti-tumor response. We find that mouse Braf V600E -driven anaplastic thyroid cancers (ATC) respond markedly to the RAF + MEK inhibitors dabrafenib and trametinib (dab/tram) and that this is associated with upregulation of MhcII in cancer cells and increased CD4+ T-cell infiltration. A subset of recurrent tumors lose MhcII expression due to silencing of Ciita , the master transcriptional regulator of MhcII, despite preserved interferon gamma signal transduction, which can be rescued by EZH2 inhibition. Orthotopically-implanted Ciita -/- and H2-Ab1 -/- ATC cells into immune competent mice become unresponsive to the MAPK inhibitors. Moreover, depletion of CD4+, but not CD8+ T-cells, also abrogates 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":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":555956,"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":0.9494,"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":13486,"name":"Ronald Ghossein","orcid":"0000-0003-2802-8489","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":45,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:55:03.976486Z","pmid":"40093098","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":[]}