Advanced Medical Technology Center, The First Affiliated Hospital-Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
Cell Rep Med. 2023 Oct 17;4(10):101229. doi: 10.1016/j.xcrm.2023.101229. Epub 2023 Oct 10.
Although promising, dendritic cell (DC) vaccines still provide limited clinical benefits, mainly due to the immunosuppressive tumor microenvironment (TME) and the lack of tumor-associated antigens (TAAs). Oncolytic virus therapy is an ideal strategy to overcome immunosuppression and expose TAAs; therefore, they may work synergistically with DC vaccines. In this study, we demonstrate that oncolytic virus M1 (OVM) can enhance the antitumor effects of DC vaccines across diverse syngeneic mouse tumor models by increasing the infiltration of CD8 effector T cells in the TME. Mechanically, we show that tumor cells counteract DC vaccines through the SIRPα-CD47 immune checkpoint, while OVM can downregulate SIRPα in DCs and CD47 in tumor cells. Since OVM upregulates PD-L1 in DCs, combining PD-L1 blockade with DC vaccines and OVM further enhances antitumor activity. Overall, OVM strengthens the antitumor efficacy of DC vaccines by targeting the SIRPα-CD47 axis, which exerts dominant immunosuppressive effects on DC vaccines.
尽管有前景，但树突状细胞 (DC) 疫苗的临床疗效仍然有限，主要是由于免疫抑制的肿瘤微环境 (TME) 和缺乏肿瘤相关抗原 (TAA)。溶瘤病毒治疗是克服免疫抑制和暴露 TAA 的理想策略；因此，它们可能与 DC 疫苗协同作用。在这项研究中，我们证明溶瘤病毒 M1 (OVM) 通过增加 TME 中 CD8 效应 T 细胞的浸润，增强了 DC 疫苗在各种同源小鼠肿瘤模型中的抗肿瘤作用。从机制上讲，我们表明肿瘤细胞通过 SIRPα-CD47 免疫检查点来对抗 DC 疫苗，而 OVM 可以下调 DC 中的 SIRPα 和肿瘤细胞中的 CD47。由于 OVM 上调了 DC 中的 PD-L1，因此与 DC 疫苗和 OVM 联合使用进一步增强了抗肿瘤活性。总的来说，OVM 通过靶向 SIRPα-CD47 轴来增强 DC 疫苗的抗肿瘤功效，该轴对 DC 疫苗具有主要的免疫抑制作用。
