Expression of Tumor Antigens within an Oncolytic Virus enhances the Anti-Tumor T Cell Response

Although patients benefit from immune checkpoint inhibition (ICI) therapy in a broad variety of tumors, resistance may arise from immune suppressive tumor microenvironments (TME), which is particularly true of hepatocellular carcinoma (HCC). Since oncolytic viruses (OV) can generate a highly immune-infiltrated, inflammatory TME, OVs could potentially restore ICI responsiveness via recruitment, priming, and activation of anti-tumor T cells. Here we find that on the contrary, an oncolytic vesicular stomatitis virus, expressing interferon-ß (VSV-IFNß), antagonizes the effect of anti-PD-L1 therapy in a partially anti-PD-L1-responsive model of HCC. Cytometry by Time of Flight shows that VSV-IFNß expands dominant anti-viral effector CD8 T cells with concomitant relative disappearance of anti-tumor T cell populations, which are the target of anti-PD-L1. However, by expressing a range of HCC tumor antigens within VSV, combination OV and anti-PD-L1 therapeutic benefit could be restored. Our data provide a cautionary message for the use of highly immunogenic viruses as tumor-specific immune-therapeutics by showing that dominant anti-viral T cell responses can inhibit sub-dominant anti-tumor T cell responses. However, through encoding tumor antigens within the virus, oncolytic virotherapy can generate anti-tumor T cell populations upon which immune checkpoint blockade can effectively work.

尽管患者可从免疫检查点抑制（immune checkpoint inhibition, ICI）疗法中获益于多种肿瘤，但免疫抑制性肿瘤微环境（tumor microenvironment, TME）可能引发耐药，这一现象在肝细胞癌（hepatocellular carcinoma, HCC）中尤为显著。溶瘤病毒（oncolytic virus, OV）可诱导形成高度免疫浸润的炎性肿瘤微环境，理论上可通过招募、致敏并激活抗肿瘤T细胞，恢复免疫检查点抑制疗法的肿瘤响应性。然而本研究却发现，表达干扰素-β（interferon-ß, IFNß）的溶瘤水疱性口炎病毒（vesicular stomatitis virus, VSV），在部分对抗PD-L1疗法存在响应的肝细胞癌模型中，会拮抗抗PD-L1治疗的效果。飞行时间流式细胞术（Cytometry by Time of Flight）检测结果显示，VSV-IFNß会扩增优势性抗病毒效应CD8 T细胞，同时伴随作为抗PD-L1治疗靶点的抗肿瘤T细胞群体相对减少。但若在VSV中编码多种肝细胞癌肿瘤抗原，则可恢复溶瘤病毒与抗PD-L1的联合治疗获益。本研究数据表明，优势性抗病毒T细胞应答可抑制亚优势抗肿瘤T细胞应答，这为将高免疫原性病毒用作肿瘤特异性免疫治疗手段提供了警示；而通过在病毒中编码肿瘤抗原，溶瘤病毒疗法可诱导产生抗肿瘤T细胞群体，此时免疫检查点阻断疗法便可有效发挥抗肿瘤作用。