MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer

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 AllonOrr 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

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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.

Original languageEnglish
Article numbere003917
JournalJournal for ImmunoTherapy of Cancer
Volume10
Issue number3
DOIs
StatePublished - 15 Mar 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2022 BMJ Publishing Group. All rights reserved.

Funding

Funding This research was funded by the DKFZ-MOST (ME and JH #001192), Israel Science Foundation (ISF, 700/16) (to ME); Israel Science Foundation (ISF, 302/21) (to ME); ISF and NSFC Israel-China project to (M.E and D.K #3409/20); the United State—Israel Binational Science Foundation (BSF, 2017323) (to ME and MS); the Israeli Cancer Research Foundation (ICRF, 17–1693-RCDA) (to ME); the Concern Foundation (#7895). Work was carried out with the help of a grant from the AFER Endowment Fund for Medical Research. LGTM is supported by the National Institutes of Health (R01 DE027738), the Sebastian Nativo Fund, the Jayme and Peter Flowers Fund; Fellowships: the Alon Fellowship to ME, Kreitman fellowship, and Midway Negev fellowship from the Ben-Gurion University of the Negev to MP. Competing interests JH was paid consultant for Bristol-Myers Squibb and MSD Sharpe & Dohme and has received other commercial research support from CureVac A G and PROGEN Biotechnik, Research funding from AstraZeneca, outside the scope of this work (to LGTM). LGTM is an inventor on a patent held by Memorial Sloan Kettering related to tumor mutational burden and immunotherapy. MS is an employee and stockholder of Astra Zeneca. JF received Honoraria from Astra Zeneca, Bristol-Myers Squibb, Merk Sharp & Dohme, Merck Serono, Innate pharma, Roche, serve as an advisor in, Astra Zeneca, Bristol-Myers Squibb, Merk Sharp & Dohme, Merck Serono, Innate pharma, Roche, has a research fund by Bristol-Myers Squibb, and had travel grants from Astra Zeneca, Bristol-Myers Squibb, Merk Sharp & Dohme.

FundersFunder number
DKFZ-MOST001192
Israeli Cancer Research Foundation17–1693-RCDA
Jayme and Peter Flowers Fund
NSFC Israel-China3409/20
Sebastian Nativo Fund
National Institutes of Health
National Institute of Dental and Craniofacial ResearchR01DE027738
Concern Foundation7895
Bristol-Myers Squibb
AstraZeneca
Meso Scale Diagnostics
United States-Israel Binational Science Foundation2017323
Israel Science Foundation700/16, 302/21
Ben-Gurion University of the Negev

    Keywords

    • Head and neck cancer
    • MEK1/2
    • anti-PD-1
    • immunotherapy
    • targeted therapy
    • tumor-immunity
    • tumor-microenvironment

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