Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.
Weill Cornell Medical College, New York, New York, USA.
J Clin Invest. 2018 Apr 2;128(4):1413-1428. doi: 10.1172/JCI98047. Epub 2018 Mar 5.
Intralesional therapy with oncolytic viruses (OVs) leads to the activation of local and systemic immune pathways, which may present targets for further combinatorial therapies. Here, we used human tumor histocultures as well as syngeneic tumor models treated with Newcastle disease virus (NDV) to identify a range of immune targets upregulated with OV treatment. Despite tumor infiltration of effector T lymphocytes in response to NDV, there was ongoing inhibition through programmed death ligand 1 (PD-L1), acting as a mechanism of early and late adaptive immune resistance to the type I IFN response and T cell infiltration, respectively. Systemic therapeutic targeting of programmed cell death receptor 1 (PD-1) or PD-L1 in combination with intratumoral NDV resulted in the rejection of both treated and distant tumors. These findings have implications for the timing of PD-1/PD-L1 blockade in conjunction with OV therapy and highlight the importance of understanding the adaptive mechanisms of immune resistance to specific OVs for the rational design of combinatorial approaches using these agents.
溶瘤病毒（OVs）的瘤内治疗会激活局部和全身免疫途径，这可能为进一步的联合治疗提供靶点。在这里，我们使用人类肿瘤组织培养物以及用新城疫病毒（NDV）治疗的同源肿瘤模型，来鉴定一系列与 OV 治疗相关的上调免疫靶点。尽管 NDV 会引发效应 T 淋巴细胞浸润肿瘤，但通过程序性死亡配体 1（PD-L1）持续抑制，这分别是对 I 型 IFN 反应和 T 细胞浸润的早期和晚期适应性免疫抵抗的机制。系统地靶向程序性细胞死亡受体 1（PD-1）或 PD-L1 联合肿瘤内 NDV 治疗可导致治疗和远处肿瘤的消退。这些发现对 PD-1/PD-L1 阻断与 OV 治疗联合使用的时机具有重要意义，并强调了为合理设计使用这些药物的联合方法，了解针对特定 OV 的适应性免疫抵抗机制的重要性。
