MEK inhibition overcomes chemoimmunotherapy resistance by inducing CXCL10 in cancer cells.
Fiche publication
Date publication
janvier 2022
Journal
Cancer cell
Auteurs
Membres identifiés du Cancéropôle Est :
Dr ARNOULD Laurent, Dr COUDERT Bruno, Pr GHIRINGHELLI François, Dr LADOIRE Sylvain, Mme TRUNTZER Caroline, Dr COLLIN Bertrand, Dr REBE Cédric, Dr FAVIER Laure, Pr CALLANAN Mary, Dr LIMAGNE Emeric, Dr BELLAYE Pierre-Simon, Dr DERANGERE Valentin, Dr FUMET Jean-David, Dr AUCAGNE Romain, Dr THIBAUDIN Marion
Tous les auteurs :
Limagne E, Nuttin L, Thibaudin M, Jacquin E, Aucagne R, Bon M, Revy S, Barnestein R, Ballot E, Truntzer C, Derangère V, Fumet JD, Latour C, Rébé C, Bellaye PS, Kaderbhaï CG, Spill A, Collin B, Callanan MB, Lagrange A, Favier L, Coudert B, Arnould L, Ladoire S, Routy B, Joubert P, Ghiringhelli F
Lien Pubmed
Résumé
Chemotherapy with anti PD-1/PD-L1 antibodies has become the standard of care for patients with metastatic non-small cell lung cancer (mNSCLC). Using lung tumor models, where pemetrexed and cisplatin (PEM/CDDP) chemotherapy remains unable to synergize with immune checkpoint inhibitors (ICIs), we linked the failure of this treatment with its inability to induce CXCL10 expression and CD8 T cell recruitment. Using drug screening, we showed that combining a MEK inhibitor (MEKi) with PEM/CDDP triggers CXCL10 secretion by cancer cells and CD8 T cell recruitment, sensitizing it to ICIs. PEM/CDDP plus a MEKi promotes optineurin (OPTN)-dependent mitophagy, resulting in CXCL10 production in a mitochondrial DNA- and TLR9-dependent manner. TLR9 or autophagy/mitophagy inhibition abolishes the anti-tumor efficacy of PEM/CDDP plus MEKi/anti-PD-L1 therapy. In human NSCLCs, high OPTN, TLR9, and CXCL10 expression is associated with a better response to ICIs. Our results underline the role of TLR9- and OPTN-dependent mitophagy in enhancing chemoimmunotherapy efficacy.
Mots clés
CXCL10, MEK inhibitor, TLR9, chemotherapy, immunogenic cell death, immunotherapy, lung cancer, mitophagy
Référence
Cancer Cell. 2022 Jan 17;: