MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer
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...
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BMJ Publishing Group
2022-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/3/e003917.full |
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| author | Barak Rotblat Andreas Mock Jerome Fayette Limor Cohen Idan Cohen Elena Voronov Jebrane Bouaoud Lucas Michon Pierre Saintigny Luc G T Morris Manu Prasad Jonathan Zorea Sankar Jagadeeshan Avital B Shnerb Sooraj Mathukkada Ofra Novoplansky Mai Badarni Ksenia M Yegodayev Sapir Tzadok Libor Brezina Andy Karabajakian Tomer Cooks Irit Allon Orr Dimitstein Benzion Joshua Dexin Kong Maurizio Scaltriti Yaron Carmi Cristina Conde-Lopez Jochen Hess Ina Kurth Moshe Elkabets |
| author_facet | Barak Rotblat Andreas Mock Jerome Fayette Limor Cohen Idan Cohen Elena Voronov Jebrane Bouaoud Lucas Michon Pierre Saintigny Luc G T Morris Manu Prasad Jonathan Zorea Sankar Jagadeeshan Avital B Shnerb Sooraj Mathukkada Ofra Novoplansky Mai Badarni Ksenia M Yegodayev Sapir Tzadok Libor Brezina Andy Karabajakian Tomer Cooks Irit Allon Orr Dimitstein Benzion Joshua Dexin Kong Maurizio Scaltriti Yaron Carmi Cristina Conde-Lopez Jochen Hess Ina Kurth Moshe Elkabets |
| author_sort | Barak Rotblat |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e52b0f83da384bc987314eeb1cc6f2e4 |
| institution | DOAJ |
| issn | 2051-1426 |
| language | English |
| publishDate | 2022-03-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-e52b0f83da384bc987314eeb1cc6f2e42025-08-20T03:05:14ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-03-0110310.1136/jitc-2021-003917MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancerBarak Rotblat0Andreas Mock1Jerome Fayette2Limor Cohen3Idan Cohen4Elena Voronov5Jebrane Bouaoud6Lucas Michon7Pierre Saintigny8Luc G T Morris9Manu Prasad10Jonathan Zorea11Sankar Jagadeeshan12Avital B Shnerb13Sooraj Mathukkada14Ofra Novoplansky15Mai Badarni16Ksenia M Yegodayev17Sapir Tzadok18Libor Brezina19Andy Karabajakian20Tomer Cooks21Irit Allon22Orr Dimitstein23Benzion Joshua24Dexin Kong25Maurizio Scaltriti26Yaron Carmi27Cristina Conde-Lopez28Jochen Hess29Ina Kurth30Moshe Elkabets31Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, IsraelDepartment of Medical Oncology, Heidelberg University Hospital, Heidelberg, GermanyMedicine Department, Centre Leon Berard, Lyon, FranceThe Shraga Segal Department of Microbiology, Immunology, and Genetics, Ben-Gurion University of the Negev, Beer-Sheva, IsraelThe Shraga Segal Department of Microbiology, Immunology, and Genetics, Ben-Gurion University of the Negev, Beer-Sheva, IsraelThe Shraga Segal Department of Microbiology, Immunology, and Genetics, Ben-Gurion University of the Negev, Beer-Sheva, IsraelUniv Lyon, Université Claude Bernard Lyon, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon 69373, FranceUniv Lyon, Université Claude Bernard Lyon, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon 69373, FranceDepartment of Translational Medicine Oncology, Centre Léon Bérard, Lyon 69373, FranceDepartment of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USAThe Shraga Segal Department of Microbiology, Immunology, and Genetics, Ben-Gurion University of the Negev, Beer-Sheva, IsraelThe Shraga Segal Department of Microbiology, Immunology, and Genetics, Ben-Gurion University of the Negev, Beer-Sheva, IsraelThe Shraga Segal Department of Microbiology, Immunology, and Genetics, Ben-Gurion University of the Negev, Beer-Sheva, IsraelThe Shraga Segal Department of Microbiology, Immunology, and Genetics, Ben-Gurion University of the Negev, Beer-Sheva, IsraelFaculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, IsraelThe Shraga Segal Department of Microbiology, Immunology, and Genetics, Ben-Gurion University of the Negev, Beer-Sheva, IsraelThe Shraga Segal Department of Microbiology, Immunology, and Genetics, Ben-Gurion University of the Negev, Beer-Sheva, IsraelThe Shraga Segal Department of Microbiology, Immunology, and Genetics, Ben-Gurion University of the Negev, Beer-Sheva, IsraelThe Shraga Segal Department of Microbiology, Immunology, and Genetics, Ben-Gurion University of the Negev, Beer-Sheva, IsraelThe Shraga Segal Department of Microbiology, Immunology, and Genetics, Ben-Gurion University of the Negev, Beer-Sheva, IsraelDepartment of Translational Medicine Oncology, Centre Léon Bérard, Lyon 69373, FranceThe Shraga Segal Department of Microbiology, Immunology, and Genetics, Ben-Gurion University of the Negev, Beer-Sheva, IsraelFaculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, IsraelFaculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, IsraelFaculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, IsraelSchool of Pharmaceutical Sciences, Tianjin Medical University, Tianjin, ChinaHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York City, New York, USADepartment of Pathology, Tel Aviv University, Tel Aviv, IsraelDivision of Radiooncology-Radiobiology, German Cancer Research Center (DKFZ), Heidelberg, GermanySection Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, GermanyDivision of Radiooncology-Radiobiology, German Cancer Research Center (DKFZ), Heidelberg, GermanyThe Shraga Segal Department of Microbiology, Immunology, and Genetics, Ben-Gurion University of the Negev, Beer-Sheva, IsraelBackground 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.https://jitc.bmj.com/content/10/3/e003917.full |
| spellingShingle | Barak Rotblat Andreas Mock Jerome Fayette Limor Cohen Idan Cohen Elena Voronov Jebrane Bouaoud Lucas Michon Pierre Saintigny Luc G T Morris Manu Prasad Jonathan Zorea Sankar Jagadeeshan Avital B Shnerb Sooraj Mathukkada Ofra Novoplansky Mai Badarni Ksenia M Yegodayev Sapir Tzadok Libor Brezina Andy Karabajakian Tomer Cooks Irit Allon Orr Dimitstein Benzion Joshua Dexin Kong Maurizio Scaltriti Yaron Carmi Cristina Conde-Lopez Jochen Hess Ina Kurth Moshe Elkabets MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer Journal for ImmunoTherapy of Cancer |
| title | MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer |
| title_full | MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer |
| title_fullStr | MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer |
| title_full_unstemmed | MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer |
| title_short | MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer |
| title_sort | mek1 2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer |
| url | https://jitc.bmj.com/content/10/3/e003917.full |
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