Zhang Hailin, Zhang Yonghui, Dong Jie, Li Binghua, Xu Chun, Wei Min, Wu Junhua, Wei Jiwu
Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China.
National Institute of Healthcare Data Science at Nanjing University, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China.
Mol Ther Oncolytics. 2020 Nov 17;20:12-22. doi: 10.1016/j.omto.2020.11.001. eCollection 2021 Mar 26.
Oncolytic virotherapy (OVT) has been suggested to be effective. However, the suppressive effects of checkpoints and insufficient costimulatory signals limit OVT-induced antitumor immune responses. In this study, we constructed a replicative adenovirus, Ad5sPVR, that expresses the soluble extracellular domain of poliovirus receptor (sPVR). We showed that sPVR can bind to both T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) and CD226, and the binding affinity of sPVR to TIGIT is stronger than that of PVR to CD226. In the H22 hepatocellular carcinoma (HCC) ascites model, Ad5sPVR treatment increased the infiltration of CD8 T cells and the release of interferon (IFN)-γ, exhibiting an antitumor effect with long-term tumor-specific immune surveillance. In line with this, Ad5sPVR also effectively improved antitumor outcomes in solid tumors. In conclusion, while Ad5sPVR plays a role in oncolysis and transforms cold tumors into hot tumors, sPVR expressed by Ad5sPVR can block the PVR/TIGIT checkpoint and activate CD226, thereby greatly improving the efficacy of OVT. This study provides a new way to develop potential oncolytic viral drugs.
溶瘤病毒疗法（OVT）已被证明是有效的。然而，检查点的抑制作用和共刺激信号不足限制了OVT诱导的抗肿瘤免疫反应。在本研究中，我们构建了一种复制型腺病毒Ad5sPVR，它表达脊髓灰质炎病毒受体的可溶性细胞外结构域（sPVR）。我们发现sPVR能同时结合T细胞免疫球蛋白和基于免疫受体酪氨酸的抑制基序结构域（TIGIT）以及CD226，且sPVR与TIGIT的结合亲和力强于PVR与CD226的结合亲和力。在H22肝癌（HCC）腹水模型中，Ad5sPVR治疗增加了CD8 T细胞浸润和干扰素（IFN）-γ释放，展现出具有长期肿瘤特异性免疫监视的抗肿瘤作用。与此一致，Ad5sPVR在实体瘤中也有效改善了抗肿瘤效果。总之，虽然Ad5sPVR在溶瘤中发挥作用并将冷肿瘤转变为热肿瘤，但Ad5sPVR表达的sPVR可阻断PVR/TIGIT检查点并激活CD226，从而大大提高OVT的疗效。本研究为开发潜在的溶瘤病毒药物提供了一种新方法。
