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Checkpoint Blockade in Combination With Doxorubicin Augments Tumor Cell Apoptosis in Osteosarcoma

Wang, Jizhuang*,†; Hu, Chuanzhen*,†; Wang, Jun; Shen, Yuhui*,†; Bao, Qiyuan*; He, Fangzhou*; Wang, Hongyi*,†; Gong, Liangzhi*,†; Liu, Zhuochao*,†; Hu, Fangqiong; Liang, Jing; Zhou, Qi; Wei, Li; Wen, Junxiang*,†; Zhang, Weibin*,†

doi: 10.1097/CJI.0000000000000281
Basic Studies
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The aim of this study was to provide a basis for the theory that the combination of conventional chemotherapy and immunotherapy would be an effective treatment for osteosarcoma. Here, the expression of programmed death ligand 1 (PD-L1) in 26 clinical osteosarcoma tissue samples collected before and after chemotherapy was analyzed. The effects of osteosarcoma cells treated with doxorubicin, a conventional chemotherapeutic agent, on the proliferation and apoptosis of CD8+ T lymphocytes were investigated in vitro. Thereafter, the effectiveness of doxorubicin combined with an anti-PD-L1 antibody as an osteosarcoma therapy was tested in 24 subcutaneous tumor mouse models. The results showed that the expression of PD-L1 was upregulated by chemotherapy in both the clinical osteosarcoma tissue samples and the osteosarcoma cell lines. The proliferation of CD8+ T lymphocytes was inhibited, and apoptosis in CD8+ T lymphocytes was enhanced by the doxorubicin-pretreated osteosarcoma cells, whereas this effect was reversed by the anti-PD-L1 antibody. A more effective result was observed when doxorubicin was combined with the anti-PD-L1 antibody in vivo. In short, the combination of conventional chemotherapy and an anti-PD-L1 antibody might be an effective option for osteosarcoma treatment, as anti-PD-L1 antibody can reverse the immunosuppression induced by chemotherapy.

*Department of Orthopaedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine

Shanghai Key Laboratory for Prevention and treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Shanghai Institute of Orthopedics and Traumatology, Shanghai, People’s Republic of China

Jizhuang Wang, C.H., and Jun Wang: contributed equally.

Reprints: Junxiang Wen and Weibin Zhang, Department of Orthopaedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijiner Road, Shanghai 200025, People’s Republic of China (e-mails: wjx372000@163.com; zhangweibin10368@163.com).

Received February 10, 2019

Accepted May 8, 2019

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