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 language | English |
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Article number | e003917 |
Journal | Journal for ImmunoTherapy of Cancer |
Volume | 10 |
Issue number | 3 |
DOIs | |
State | Published - 15 Mar 2022 |
Externally published | Yes |
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.
Funders | Funder number |
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DKFZ-MOST | 001192 |
Israeli Cancer Research Foundation | 17–1693-RCDA |
Jayme and Peter Flowers Fund | |
NSFC Israel-China | 3409/20 |
Sebastian Nativo Fund | |
National Institutes of Health | |
National Institute of Dental and Craniofacial Research | R01DE027738 |
Concern Foundation | 7895 |
Bristol-Myers Squibb | |
AstraZeneca | |
Meso Scale Diagnostics | |
United States-Israel Binational Science Foundation | 2017323 |
Israel Science Foundation | 700/16, 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