Journal
CANCER CELL
Volume 40, Issue 2, Pages 136-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2021.12.009
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Funding
- Ligue Nationale contre le Cancer (Equipes labellisees)
- Institut National du Cancer (INCa)
- Association pour la Recherche sur le Cancer (ARC)
- Fondation AMGEN
- LabEx LipSTIC
- Region Bourgogne-Franche-Comte (BFC)
- I-Site-BFC program
- French government through the French National Research Agency (ANR) under the program Investissements d'Avenir [ANR-10-EQPX-05-01/IMAPPI Equipex]
- Georges-Francois Leclerc Cancer Center
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Chemotherapy combined with MEK inhibitor enhances the sensitivity of lung cancer cells to immune checkpoint inhibitors by inducing CXCL10 expression and CD8(+) T cell recruitment. The study also highlights the role of TLR9- and OPTN-dependent mitophagy in enhancing the efficacy of chemoimmunotherapy.
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.
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