Oncolytic virotherapy can lead to systemic antitumor immunity, but the therapeutic potential of oncolytic viruses in humans is limited due to their insufficient ability to overcome the immunosuppressive tumor microenvironment (TME). Here, we showed that locoregional oncolytic virotherapy upregulated the expression of PD-L1 in the TME, which was mediated by virus-induced type I and type II IFNs. To explore PD-1/PD-L1 signaling as a direct target in tumor tissue, we developed a novel immunotherapeutic herpes simplex virus (HSV), OVH-aMPD-1, that expressed a single-chain variable fragment (scFv) against PD-1 (aMPD-1 scFv). The virus was designed to locally deliver aMPD-1 scFv in the TME to achieve enhanced antitumor effects. This virus effectively modified the TME by releasing damage-associated molecular patterns, promoting antigen cross-presentation by dendritic cells, and enhancing the infiltration of activated T cells; these alterations resulted in antitumor T-cell activity that led to reduced tumor burdens in a liver cancer model. Compared with OVH, OVH-aMPD-1 promoted the infiltration of myeloid-derived suppressor cells (MDSC), resulting in significantly higher percentages of CD155+ granulocytic-MDSCs (G-MDSC) and monocytic-MDSCs (M-MDSC) in tumors. In combination with TIGIT blockade, this virus enhanced tumor-specific immune responses in mice with implanted subcutaneous tumors or invasive tumors. These findings highlighted that intratumoral immunomodulation with an OV expressing aMPD-1 scFv could be an effective stand-alone strategy to treat cancers or drive maximal efficacy of a combination therapy with other immune checkpoint inhibitors.

中文翻译：

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肿瘤内递送PD-1阻断scFv的溶瘤HSV-1编码可促进抗肿瘤免疫力并与TIGIT阻断协同作用。

溶瘤病毒疗法可导致全身性抗肿瘤免疫，但溶瘤病毒在人类中的治疗潜力受到限制，原因是它们无法克服免疫抑制性肿瘤微环境（TME）的能力不足。在这里，我们显示局部局部溶瘤病毒疗法上调了TME中PD-L1的表达，该表达是由病毒诱导的I型和II型IFN介导的。为了探索PD-1 / PD-L1信号作为肿瘤组织中的直接靶标，我们开发了一种新型的免疫治疗性单纯疱疹病毒（HSV）OVH-aMPD-1，它表达了针对PD-的单链可变片段（scFv） 1（aMPD-1 scFv）。该病毒旨在在TME中局部递送aMPD-1 scFv，以增强抗肿瘤作用。该病毒通过释放与损伤相关的分子模式，有效地修饰了TME，促进树突状细胞的抗原交叉呈递，并增强活化的T细胞的浸润；这些改变导致抗肿瘤T细胞活性降低了肝癌模型的肿瘤负担。与OVH相比，OVH-aMPD-1促进了髓样抑制细胞（MDSC）的浸润，导致肿瘤中CD155 +粒细胞-MDSCs（G-MDSC）和单核细胞-MDSCs（M-MDSC）的百分比明显更高。结合TIGIT阻断，这种病毒可增强植入皮下肿瘤或浸润性肿瘤的小鼠的肿瘤特异性免疫反应。这些发现强调，用表达aMPD-1 scFv的OV进行肿瘤内免疫调节可能是治疗癌症或推动与其他免疫检查点抑制剂联合治疗的最大疗效的有效独立策略。