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Article Dans Une Revue Journal for Immunotherapy of Cancer Année : 2022

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

Manu Prasad
  • Fonction : Auteur
Jonathan Zorea
  • Fonction : Auteur
Sankar Jagadeeshan
  • Fonction : Auteur
Avital Shnerb
  • Fonction : Auteur
Sooraj Mathukkada
  • Fonction : Auteur
Jebrane Bouaoud
  • Fonction : Auteur
Lucas Michon
  • Fonction : Auteur
Ofra Novoplansky
  • Fonction : Auteur
Mai Badarni
  • Fonction : Auteur
Limor Cohen
  • Fonction : Auteur
Ksenia Yegodayev
  • Fonction : Auteur
Sapir Tzadok
  • Fonction : Auteur
Barak Rotblat
  • Fonction : Auteur
Libor Brezina
  • Fonction : Auteur
Andreas Mock
  • Fonction : Auteur
Idan Cohen
  • Fonction : Auteur
Tomer Cooks
  • Fonction : Auteur
Irit Allon
  • Fonction : Auteur
Orr Dimitstein
  • Fonction : Auteur
Benzion Joshua
  • Fonction : Auteur
Dexin Kong
  • Fonction : Auteur
Elena Voronov
  • Fonction : Auteur
Maurizio Scaltriti
  • Fonction : Auteur
Yaron Carmi
  • Fonction : Auteur
Cristina Conde-Lopez
  • Fonction : Auteur
Jochen Hess
  • Fonction : Auteur
Ina Kurth
  • Fonction : Auteur
Luc Morris
  • Fonction : Auteur
Moshe Elkabets

Résumé

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.

Dates et versions

hal-03865108 , version 1 (22-11-2022)

Identifiants

Citer

Manu Prasad, Jonathan Zorea, Sankar Jagadeeshan, Avital Shnerb, Sooraj Mathukkada, et al.. MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer. Journal for Immunotherapy of Cancer, 2022, 10 (3), pp.e003917. ⟨10.1136/jitc-2021-003917⟩. ⟨hal-03865108⟩
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