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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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
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March 15, 2022
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| In: |
Journal for ImmunoTherapy of Cancer
Year: 2022, Jahrgang: 10, Heft: 3, Pages: 1-16 |
| ISSN: | 2051-1426 |
| DOI: | 10.1136/jitc-2021-003917 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1136/jitc-2021-003917 Verlag, lizenzpflichtig, Volltext: https://jitc.bmj.com/content/10/3/e003917 
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| Verfasserangaben: | Manu Prasad, Jonathan Zorea, Sankar Jagadeeshan, Avital B Shnerb, Sooraj Mathukkada, Jebrane Bouaoud, Lucas Michon, Ofra Novoplansky, Mai Badarni, Limor Cohen, Ksenia M Yegodayev, Sapir Tzadok, Barak Rotblat, Libor Brezina, Andreas Mock, Andy Karabajakian, Jérôme Fayette, Idan Cohen, Tomer Cooks, Irit Allon, Orr Dimitstein, Benzion Joshua, Dexin Kong, Elena Voronov, Maurizio Scaltriti, Yaron Carmi, Cristina Conde-Lopez, Jochen Hess, Ina Kurth, Luc G T Morris, Pierre Saintigny, Moshe Elkabets |
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| 245 | 1 | 0 | |a MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer |c Manu Prasad, Jonathan Zorea, Sankar Jagadeeshan, Avital B Shnerb, Sooraj Mathukkada, Jebrane Bouaoud, Lucas Michon, Ofra Novoplansky, Mai Badarni, Limor Cohen, Ksenia M Yegodayev, Sapir Tzadok, Barak Rotblat, Libor Brezina, Andreas Mock, Andy Karabajakian, Jérôme Fayette, Idan Cohen, Tomer Cooks, Irit Allon, Orr Dimitstein, Benzion Joshua, Dexin Kong, Elena Voronov, Maurizio Scaltriti, Yaron Carmi, Cristina Conde-Lopez, Jochen Hess, Ina Kurth, Luc G T Morris, Pierre Saintigny, Moshe Elkabets |
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| 520 | |a 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. | ||
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| 650 | 4 | |a immunotherapy | |
| 650 | 4 | |a MEK1/2 | |
| 650 | 4 | |a targeted therapy | |
| 650 | 4 | |a tumor-immunity | |
| 650 | 4 | |a tumor-microenvironment | |
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