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Mitophagy: a new actor in the efficacy of chemo-immunotherapy

Emeric Limagne1,2,3,4, François Ghiringhelli1,2,3,4,5

  • 1Cancer Biology Transfer Platform, Centre Georges-François Leclerc, Equipe Labellisée Ligue Contre le Cancer, Dijon, France.

Autophagy
|May 9, 2022
PubMed

Insights

MAPK pathway inhibition overcomes chemo-immunotherapy resistance in non-small cell lung cancer. This approach enhances cancer cell mitophagy and promotes T cell recruitment, improving treatment efficacy.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Chemo-immunotherapy resistance is a significant challenge in treating non-small cell lung cancer (NSCLC).
  • The Mitogen-Activated Protein Kinase (MAPK) pathway is implicated in limiting the effectiveness of current cancer therapies.

Purpose of the Study:

  • To investigate the role of the MAPK pathway in chemo-immunotherapy resistance in NSCLC.
  • To explore the potential of inhibiting the MAPK pathway to enhance therapeutic outcomes.

Main Methods:

  • Utilized a MAP2K/MEK inhibitor in combination with chemotherapy.
  • Investigated optineurin (OPTN)-dependent mitophagy, mitochondrial DNA release, Toll-like receptor 9 (TLR9) activation, and CXCL10 chemokine production.

Main Results:

  • MAPK pathway inhibition promoted OPTN-dependent mitophagy of cancer cells.
  • Released mitochondrial DNA activated TLR9, leading to CXCL10 production.
  • CXCL10 enhanced T cell recruitment, improving immunotherapy efficacy.

Conclusions:

  • Inhibiting the MAPK pathway is a promising strategy to overcome chemo-immunotherapy resistance in NSCLC.
  • The mechanism involves enhanced mitophagy, TLR9 activation, and subsequent T cell recruitment.
  • This approach could significantly improve treatment outcomes for NSCLC patients.
Keywords:
CXCL10ChemotherapyMAP2K/MEK inhibitorTLR9ULK1immunotherapymitophagyoptineurin

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