法国勃艮第-弗朗什孔泰大学François Ghiringhelli、Emeric Limagne等研究人员合作发现，抑制MEK通过诱导癌细胞的CXCL10来克服化疗免疫疗法的耐药性。这一研究成果于2022年1月19日在线发表于国际学术期刊《癌细胞》。

Author: Emeric Limagne, Lisa Nuttin, Marion Thibaudin, Elise Jacquin, Romain Aucagne, Marjorie Bon, Solène Revy, Robby Barnestein, Elise Ballot, Caroline Truntzer, Valentin Derangère, Jean-David Fumet, Charlène Latour, Cédric Rébé, Pierre-Simon Bellaye, Coureche-Guillaume Kaderbha, Aodrenn Spill, Bertrand Collin, Mary B. Callanan, Aurélie Lagrange, Laure Favier, Bruno Coudert, Laurent Arnould, Sylvain Ladoire, Bertrand Routy, Philippe Joubert, Franois Ghiringhelli

Issue&Volume: 2022-01-19

Abstract: Chemotherapy with anti PD-1/PD-L1 antibodies has become the standard of care for patientswith metastatic non-small cell lung cancer (mNSCLC). Using lung tumor models, wherepemetrexed and cisplatin (PEM/CDDP) chemotherapy remains unable to synergize withimmune checkpoint inhibitors (ICIs), we linked the failure of this treatment withits 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)-dependentmitophagy, resulting in CXCL10 production in a mitochondrial DNA- and TLR9-dependentmanner. TLR9 or autophagy/mitophagy inhibition abolishes the anti-tumor efficacy ofPEM/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 therole of TLR9- and OPTN-dependent mitophagy in enhancing chemoimmunotherapy efficacy.

DOI: 10.1016/j.ccell.2021.12.009

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00662-0