MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer. Issue 3 (15th March 2022)

• Record Type: Journal Article
• Authors: Prasad, Manu; Zorea, Jonathan; Jagadeeshan, Sankar; Shnerb, Avital B; Mathukkada, Sooraj; Bouaoud, Jebrane; Michon, Lucas; Novoplansky, Ofra; Badarni, Mai; Cohen, Limor; Yegodayev, Ksenia M; Tzadok, Sapir; Rotblat, Barak; Brezina, Libor; Mock, Andreas; Karabajakian, Andy; Fayette, Jérôme; Cohen, Idan; Cooks, Tomer; Allon, Irit; Dimitstein, Orr; Joshua, Benzion; Kong, Dexin; Voronov, Elena; Scaltriti, Maurizio; Carmi, Yaron; Conde-Lopez, Cristina; Hess, Jochen; Kurth, Ina; Morris, Luc G T; Saintigny, Pierre; Elkabets, Moshe;
• Is Part Of: Journal for immunotherapy of cancer. Volume 10:Issue 3(2022)
• Publication Date: 2022-03-15
• Subjects: Head and neck cancer -- tumor-microenvironment -- tumor-immunity -- immunotherapy -- targeted therapy -- MEK1/2 -- anti-PD-1; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2021-003917
• Languages: English
• ISSNs: 2051-1426

Abstract

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.