{"doi":"10.1136/jitc-2021-003917","title":"MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer","abstract":"Background Although the mitogen-activated protein kinases (MAPK) pathway is hyperactive in head and neck cancer (HNC), inhibition of MEK1/2 in HNC patients has not shown clinically meaningful activity. Therefore, we aimed to characterize the effect of MEK1/2 inhibition on the tumor microenvironment (TME) of MAPK-driven HNC, elucidate tumor-host interaction mechanisms facilitating immune escape on treatment, and apply rationale-based therapy combination immunotherapy and MEK1/2 inhibitor to induce tumor clearance. Methods Mouse syngeneic tumors and xenografts experiments were used to analyze tumor growth in vivo. Single-cell cytometry by time of flight, flow cytometry, and tissue stainings were used to profile the TME in response to trametinib (MEK1/2 inhibitor). Co-culture of myeloid-derived suppressor cells (MDSC) with CD8 + T cells was used to measure immune suppression. Overexpression of colony-stimulating factor-1 (CSF-1) in tumor cells was used to show the effect of tumor-derived CSF-1 on sensitivity to trametinib and anti-programmed death- 1 (αPD-1) in mice. In HNC patients, the ratio between CSF-1 and CD8A was measured to test the association with clinical benefit to αPD-1 and αPD-L1 treatment. Results Using preclinical HNC models, we demonstrated that treatment with trametinib delays HNC initiation and progression by reducing tumor cell proliferation and enhancing the antitumor immunity of CD8 + T cells. Activation of CD8 + T cells by supplementation with αPD-1 antibody eliminated tumors and induced an immune memory in the cured mice. Mechanistically, an early response to trametinib treatment sensitized tumors to αPD-1-supplementation by attenuating the expression of tumor-derived CSF-1, which reduced the abundance of two CSF-1R + CD11c + MDSC populations in the TME. In contrast, prolonged treatment with trametinib abolished the antitumor activity of αPD-1, because tumor cells undergoing the epithelial to mesenchymal transition in response to trametinib restored CSF-1 expression and recreated an immune-suppressive TME. Conclusion Our findings provide the rationale for testing the trametinib/αPD-1 combination in HNC and highlight the importance of sensitizing tumors to αPD-1 by using MEK1/2 to interfere with the tumor–host interaction. Moreover, we describe the concept that treatment of cancer with a targeted therapy transiently induces an immune-active microenvironment, and supplementation of immunotherapy during this time further activates the antitumor machinery to cause tumor elimination.","journal":"Journal for ImmunoTherapy of Cancer","year":2022,"id":236290,"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":70,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9679,"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":817766,"name":"Jonathan Zorea","orcid":"0000-0002-8602-8869","position":1,"is_corresponding":false},{"id":308703,"name":"Sankar Jagadeeshan","orcid":"0000-0002-3778-8757","position":2,"is_corresponding":false},{"id":817767,"name":"Avital Beeri Shnerb","orcid":"0000-0002-7780-9217","position":3,"is_corresponding":false},{"id":856183,"name":"Sooraj Mathukkada","orcid":"0000-0002-0210-2399","position":4,"is_corresponding":false},{"id":817768,"name":"Jebrane Bouaoud","orcid":"0000-0003-2964-2579","position":5,"is_corresponding":false},{"id":817769,"name":"Lucas Michon","orcid":"0000-0002-1839-4656","position":6,"is_corresponding":false},{"id":308702,"name":"Ofra Novoplansky","orcid":"0000-0002-1239-7856","position":7,"is_corresponding":false},{"id":733745,"name":"Mai Badarni","orcid":"0000-0002-4413-2932","position":8,"is_corresponding":false},{"id":733751,"name":"Limor Cohen","orcid":"0009-0003-8302-4269","position":9,"is_corresponding":false},{"id":733749,"name":"Ksenia M. Yegodayev","orcid":"0000-0003-0721-838X","position":10,"is_corresponding":false},{"id":818479,"name":"Sapir Tzadok","orcid":null,"position":11,"is_corresponding":false},{"id":17925,"name":"Barak Rotblat","orcid":"0000-0003-2985-7115","position":12,"is_corresponding":false},{"id":818480,"name":"Libor Brezina","orcid":null,"position":13,"is_corresponding":false},{"id":817770,"name":"Andreas Möck","orcid":"0000-0002-3332-9166","position":14,"is_corresponding":false},{"id":818481,"name":"Andy Karabajakian","orcid":null,"position":15,"is_corresponding":false},{"id":1550,"name":"Jérôme Fayette","orcid":"0000-0002-8126-7019","position":16,"is_corresponding":false},{"id":707419,"name":"Idan Cohen","orcid":"0000-0002-5524-2344","position":17,"is_corresponding":false},{"id":817771,"name":"Tomer Cooks","orcid":"0000-0003-0853-3437","position":18,"is_corresponding":false},{"id":817772,"name":"Irit Allon","orcid":"0000-0003-1861-0782","position":19,"is_corresponding":false},{"id":734357,"name":"Orr Dimitstein","orcid":null,"position":20,"is_corresponding":false},{"id":733750,"name":"Ben‐Zion Joshua","orcid":"0000-0002-2010-892X","position":21,"is_corresponding":false},{"id":434386,"name":"Dexin Kong","orcid":"0000-0002-8064-1435","position":22,"is_corresponding":false},{"id":817773,"name":"Elena Voronov","orcid":"0000-0001-8453-3215","position":23,"is_corresponding":false},{"id":52651,"name":"Maurizio Scaltriti","orcid":"0000-0002-5522-1447","position":24,"is_corresponding":false},{"id":232886,"name":"Yaron Carmi","orcid":"0000-0002-0972-0616","position":25,"is_corresponding":false},{"id":856184,"name":"Cristina Conde‐López","orcid":"0000-0001-9928-790X","position":26,"is_corresponding":false},{"id":817774,"name":"Jochen Heß","orcid":"0000-0003-3493-1711","position":27,"is_corresponding":false},{"id":856185,"name":"Ina Kurth","orcid":"0000-0001-9261-5165","position":28,"is_corresponding":false},{"id":90772,"name":"Luc G.T. Morris","orcid":"0000-0002-4417-2280","position":29,"is_corresponding":false},{"id":305872,"name":"Pierre Saintigny","orcid":"0000-0002-8090-9323","position":30,"is_corresponding":false},{"id":308706,"name":"Moshe Elkabets","orcid":"0000-0003-3634-9098","position":31,"is_corresponding":false},{"id":733746,"name":"Manu Prasad","orcid":"0000-0001-7690-3511","position":0,"is_corresponding":true}],"reference_count":79,"raw_metadata":null,"created_at":"2026-07-19T00:21:58.728756Z","pmid":"35292516","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":[]}