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Targeting autophagy enhances atezolizumab-induced mitochondria-related apoptosis in osteosarcoma

Zhuochao Liu1, Hongyi Wang1, Chuanzhen Hu2

  • 1Department of Orthopedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Cell Death & Disease
|February 9, 2021
PubMed

Insights

Atezolizumab triggers cancer cell death via mitochondrial damage and apoptosis, independent of immune response. Combining it with autophagy inhibitors enhances its tumor-suppressing effects.

Area of Science:

  • Immunology
  • Oncology
  • Cell Biology

Background:

  • Atezolizumab targets PD-L1, a protein involved in immune evasion.
  • Its efficacy in tumor suppression, beyond immune restoration, requires further investigation.

Purpose of the Study:

  • To elucidate the immune-independent mechanisms of atezolizumab in osteosarcoma.
  • To explore strategies for enhancing atezolizumab's anti-tumor efficacy.

Main Methods:

  • In vitro and in vivo studies using osteosarcoma cell lines and animal models.
  • Analysis of cellular apoptosis, mitochondrial function, reactive oxygen species (ROS) production, and autophagy.
  • Combination therapy with atezolizumab and autophagy inhibitors (e.g., chloroquine).

Main Results:

  • Atezolizumab inhibited osteosarcoma cell proliferation and induced immune-independent apoptosis.
  • Mitochondrial impairment, increased ROS and cytochrome-c release, and JNK pathway activation were observed.
  • Atezolizumab induced protective autophagy, which counteracted its cytotoxic effects.
  • Combining atezolizumab with autophagy inhibitors significantly enhanced its anti-cancer activity in vitro and in vivo.

Conclusions:

  • Atezolizumab induces mitochondrial-mediated apoptosis and protective autophagy in osteosarcoma cells, independent of immune modulation.
  • Targeting autophagy presents a promising strategy to potentiate atezolizumab's anti-tumor cytotoxicity.

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