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.
Department of Orthopaedics, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China.
Cell Death Dis. 2021 Feb 8;12(2):164. doi: 10.1038/s41419-021-03449-6.
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.
在这项研究中，我们发现了抗 PD-L1 单克隆抗体阿替利珠单抗（atezolizumab）的多方面作用，除了恢复抗肿瘤免疫外，还能抑制肿瘤生长，我们还研究了提高其疗效的有前景的方法。阿替利珠单抗可以抑制骨肉瘤细胞的增殖并诱导免疫非依赖性细胞凋亡。通过进一步研究，我们发现阿替利珠单抗可以损害骨肉瘤细胞的线粒体，导致活性氧和细胞色素-c 的释放增加，最终通过激活 JNK 通路导致线粒体相关的细胞凋亡。然而，活性氧的过度释放也激活了骨肉瘤细胞的保护性自噬。因此，当我们将阿替利珠单抗与自噬抑制剂联合使用时，阿替利珠单抗对骨肉瘤细胞的细胞毒性作用在体外显著增强。进一步的体内实验也证实，阿替利珠单抗联合氯喹可达到最显著的抗肿瘤效果。总之，我们的研究表明，阿替利珠单抗可以独立于免疫系统诱导线粒体相关的凋亡和保护性自噬，靶向自噬是增强其细胞毒性的一种很有前途的联合治疗方法。
