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Parkin modulates the hepatocellular carcinoma microenvironment by regulating PD-1/PD-L1 signalling

  • 0Clinical Laboratory, The Yuhuan People's Hospital, Taizhou 317600, China; Cancer Center, Department of Medical Oncology, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, China.
Journal of Advanced Research +

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January 4, 2025

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January 4, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

Parkin deficiency impairs liver cancer immunity by reducing mitophagy and increasing PD-1 expression. Restoring Parkin or mitophagy may enhance anti-tumour responses and immunotherapy for HCC.

Area Of Science

  • Immunology
  • Oncology
  • Cell Biology

Background

  • Parkin-mediated mitophagy is crucial for clearing damaged mitochondria and inhibiting tumor development.
  • The role of mitophagy in tumor immunity is increasingly recognized, but mechanisms remain unclear.

Purpose Of The Study

  • To investigate Parkin's role in the immune microenvironment of carbon tetrachloride-induced liver tumors.
  • To elucidate the mechanism by which Parkin influences tumor immunity via PD-1 expression.

Main Methods

  • Single-cell RNA sequencing of T lymphocytes and myeloid-derived cells.
  • Western blot, immunofluorescence, and co-immunoprecipitation.
  • Quantitative proteomic analysis.

Main Results

  • Parkin deficiency (Park2-/-) in mice led to severe liver damage, increased malignancy, and an immunosuppressive tumor microenvironment.
  • Reduced cytotoxic CD8+ T cells and increased exhausted CD8+ T cells (PD-1+, Lag3+, Tigit+) were observed in Park2-/- mice.
  • Increased M2-like macrophages and differential protein expression related to PD-1 and antigen presentation pathways were found in Parkin-deficient livers.
  • Parkin deficiency decreased hepatic mitophagy, promoting liver cancer by creating an immunosuppressive microenvironment.

Conclusions

  • Parkin, an E3 ubiquitin ligase, degrades PD-1 in liver cancer, influencing anti-tumor immunity via the PD-1/PD-L1 pathway.
  • Reintroducing Parkin or enhancing mitophagy can remodel the tumor microenvironment, activating anti-tumor immunity.
  • Targeting Parkin or mitophagy presents a promising strategy to improve immunotherapy efficacy in hepatocellular carcinoma (HCC).

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