MEK inhibition overcomes chemoimmunotherapy resistance by inducing CXCL10 in cancer cells.

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. [Display omitted] • MEK inhibition synergizes with chemotherapy to induce CD8+ T cell recruitment in TME • Active KRAS-MEK pathway negatively regulates optineurin-dependent mitophagy • TLR9-dependent mitochondrial DNA sensing during mitophagy induces CXCL10 expression • MEK inhibitor and chemotherapy combination synergizes with PD-L1 blockade Limagne et al. show that simultaneous treatment by chemotherapy and MEK inhibitors promotes mitophagy and mitochondrial DNA recognition by TLR9. TLR9 signaling leads to CXCL10 expression in cancer cells and CD8+ T cell recruitment to tumors and improves efficacy of PD-L1 blockade. [ABSTRACT FROM AUTHOR]