Journal Article

DKFZ-2022-00503

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer.

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.DKFZ* ; 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.DKFZ* ; Hess, J.DKFZ* ; Kurth, I.DKFZ* ; Morris, L. G. T. ; Saintigny, P. ; Elkabets, M.

2022
BioMed Central London

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Please use a persistent id in citations: doi:10.1136/jitc-2021-003917

Abstract: 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.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.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.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.

Keyword(s): Head and neck cancer ; MEK1/2 ; anti-PD-1 ; immunotherapy ; targeted therapy ; tumor-immunity ; tumor-microenvironment

Note: #DKFZ-MOST-Ca204#

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Contributing Institute(s):

1. Translationale Medizinische Onkologie (B340)
2. Molekulare Grundlagen von HNO-Tumoren (E221)
3. E220 Radioonkologie Radiobiologie (E220)

Research Program(s):

1. 315 - Bildgebung und Radioonkologie (POF4-315) (POF4-315)

Appears in the scientific report 2022

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