RT Journal Article
SR Electronic
T1 MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e003917
DO 10.1136/jitc-2021-003917
VO 10
IS 3
A1 Prasad, Manu
A1 Zorea, Jonathan
A1 Jagadeeshan, Sankar
A1 Shnerb, Avital B
A1 Mathukkada, Sooraj
A1 Bouaoud, Jebrane
A1 Michon, Lucas
A1 Novoplansky, Ofra
A1 Badarni, Mai
A1 Cohen, Limor
A1 Yegodayev, Ksenia M
A1 Tzadok, Sapir
A1 Rotblat, Barak
A1 Brezina, Libor
A1 Mock, Andreas
A1 Karabajakian, Andy
A1 Fayette, Jérôme
A1 Cohen, Idan
A1 Cooks, Tomer
A1 Allon, Irit
A1 Dimitstein, Orr
A1 Joshua, Benzion
A1 Kong, Dexin
A1 Voronov, Elena
A1 Scaltriti, Maurizio
A1 Carmi, Yaron
A1 Conde-Lopez, Cristina
A1 Hess, Jochen
A1 Kurth, Ina
A1 Morris, Luc G T
A1 Saintigny, Pierre
A1 Elkabets, Moshe
YR 2022
UL http://jitc.bmj.com/content/10/3/e003917.abstract
AB 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.Data are available in a public, open access repository. Data are available on reasonable request. Raw RNA-seq data is deposited at the BioProject ID PRJNA795864.Raw RNA-seq data is deposited the BioProject ID PRJNA795864. All data are available in the main text or supplementary materials. Any data and materials that can be shared will be released via a material transfer agreement. Raw RNA-seq data is deposited at the BioProject ID PRJNA795864.