MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer Journal Article
| Authors: | Prasad, M.; Zorea, J.; Jagadeeshan, S.; Shnerb, A. B.; Mathukkada, S.; Bouaoud, J.; Michon, L.; Novoplansky, O.; Badarni, M.; Cohen, L.; Yegodayev, K. M.; Tzadok, S.; Rotblat, B.; Brezina, L.; Mock, A.; Karabajakian, A.; Fayette, J.; Cohen, I.; Cooks, T.; Allon, I.; Dimitstein, O.; Joshua, B.; Kong, D.; Voronov, E.; Scaltriti, M.; Carmi, Y.; Conde-Lopez, C.; Hess, J.; Kurth, I.; Morris, L. G. T.; Saintigny, P.; Elkabets, M. |
| Article 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. © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ. |
| Keywords: | immunotherapy; head and neck cancer; targeted therapy; tumor-immunity; anti-pd-1; tumor-microenvironment; mek1/2 |
| Journal Title: | Journal for ImmunoTherapy of Cancer |
| Volume: | 10 |
| Issue: | 3 |
| ISSN: | 2051-1426 |
| Publisher: | Biomed Central Ltd |
| Date Published: | 2022-03-01 |
| Start Page: | e003917 |
| Language: | English |
| DOI: | 10.1136/jitc-2021-003917 |
| PUBMED: | 35292516 |
| PROVIDER: | scopus |
| PMCID: | PMC8928405 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 April 2022 -- Source: Scopus |
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