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.
J Immunother. 2019 Nov/Dec;42(9):321-330. doi: 10.1097/CJI.0000000000000281.
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.
本研究旨在为常规化疗与免疫疗法联合应用于骨肉瘤治疗有效的理论提供依据。本研究分析了 26 例骨肉瘤患者化疗前后临床组织样本中程序性死亡配体 1（PD-L1）的表达情况，并体外研究了常规化疗药物阿霉素处理后的骨肉瘤细胞对 CD8+T 淋巴细胞增殖和凋亡的影响。随后，在 24 个骨肉瘤皮下肿瘤小鼠模型中测试了阿霉素联合抗 PD-L1 抗体作为骨肉瘤治疗的效果。结果表明，化疗可上调临床骨肉瘤组织样本和骨肉瘤细胞系中 PD-L1 的表达。阿霉素预处理的骨肉瘤细胞可抑制 CD8+T 淋巴细胞的增殖，促进 CD8+T 淋巴细胞的凋亡，而抗 PD-L1 抗体可逆转这一效应。体内联合应用阿霉素和抗 PD-L1 抗体可获得更有效的效果。总之，常规化疗与抗 PD-L1 抗体联合应用可能是骨肉瘤治疗的有效选择，因为抗 PD-L1 抗体可逆转化疗引起的免疫抑制。
