%0 Journal Article
%A Prasad, Manu
%A Zorea, Jonathan
%A Jagadeeshan, Sankar
%A Shnerb, Avital B
%A Mathukkada, Sooraj
%A Bouaoud, Jebrane
%A Michon, Lucas
%A Novoplansky, Ofra
%A Badarni, Mai
%A Cohen, Limor
%A Yegodayev, Ksenia M
%A Tzadok, Sapir
%A Rotblat, Barak
%A Brezina, Libor
%A Mock, Andreas
%A Karabajakian, Andy
%A Fayette, Jérôme
%A Cohen, Idan
%A Cooks, Tomer
%A Allon, Irit
%A Dimitstein, Orr
%A Joshua, Benzion
%A Kong, Dexin
%A Voronov, Elena
%A Scaltriti, Maurizio
%A Carmi, Yaron
%A Conde-Lopez, Cristina
%A Hess, Jochen
%A Kurth, Ina
%A Morris, Luc G T
%A Saintigny, Pierre
%A Elkabets, Moshe
%T MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer.
%J Journal for ImmunoTherapy of Cancer
%V 10
%N 3
%@ 2051-1426
%C London
%I BioMed Central
%M DKFZ-2022-00503
%P e003917
%D 2022
%Z #DKFZ-MOST-Ca204#
%X 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.
%K Head and neck cancer (Other)
%K MEK1/2 (Other)
%K anti-PD-1 (Other)
%K immunotherapy (Other)
%K targeted therapy (Other)
%K tumor-immunity (Other)
%K tumor-microenvironment (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:35292516
%R 10.1136/jitc-2021-003917
%U https://inrepo02.dkfz.de/record/179147