2. Academic Validation
  3. Targeting autophagy enhances atezolizumab-induced mitochondria-related apoptosis in osteosarcoma

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

  • Cell Death Dis. 2021 Feb 8;12(2):164. doi: 10.1038/s41419-021-03449-6.
Zhuochao Liu  # 1,  Hongyi Wang  # 1,  Chuanzhen Hu  # 2,  Chuanlong Wu 1,  Jun Wang 1,  Fangqiong Hu 1,  Yucheng Fu 1,  Junxiang Wen 3,  Weibin Zhang 4
Affiliations

Affiliations

  • 1 Department 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.
  • 2 Department of Orthopaedics, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China.
  • 3 Department 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. wjx372000@163.com.
  • 4 Department 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. zhangweibin10368@163.com.
  • # Contributed equally.
PMID: 33558476 DOI: 10.1038/s41419-021-03449-6
Abstract

In this study, we identified the multifaceted effects of atezolizumab, a specific monoclonal antibody against PD-L1, in tumor suppression except for restoring antitumor immunity, and investigated the promising ways to improve its efficacy. Atezolizumab could inhibit the proliferation and induce immune-independent Apoptosis of osteosarcoma cells. With further exploration, we found that atezolizumab could impair mitochondria of osteosarcoma cells, resulting in increased release of Reactive Oxygen Species and cytochrome-c, eventually leading to mitochondrial-related Apoptosis via activating JNK pathway. Nevertheless, the excessive release of Reactive Oxygen Species also activated the protective Autophagy of osteosarcoma cells. Therefore, when we combined atezolizumab with Autophagy inhibitors, the cytotoxic effect of atezolizumab on osteosarcoma cells was significantly enhanced in vitro. Further in vivo experiments also confirmed that atezolizumab combined with chloroquine achieved the most significant antitumor effect. Taken together, our study indicates that atezolizumab can induce mitochondrial-related Apoptosis and protective Autophagy independently of the immune system, and targeting Autophagy is a promising combinatorial approach to amplify its cytotoxicity.

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