PDF(Pubmed)
Abstract：
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.
摘要：
尽管患者在多种肿瘤中受益于免疫检查点抑制（ICI）治疗，耐药性可能来自免疫抑制肿瘤微环境(TME)，这是特别真实的肝细胞癌（HCC）。由于溶瘤病毒（OV）可以产生高度免疫浸润，炎性TME，OV可能会通过招募来恢复ICI的响应能力，启动,和激活抗肿瘤T细胞。在这里，我们发现相反，溶瘤性水疱性口炎病毒，表达干扰素β（VSV-IFNβ），在部分抗PD-L1反应性HCC模型中拮抗抗PD-L1治疗的效果。通过飞行时间的细胞测定法显示，VSV-IFNβ扩增显性抗病毒效应CD8T细胞，伴随着抗肿瘤T细胞群的相对消失，它们是抗PD-L1的靶标。然而,通过在VSV内表达一系列HCC肿瘤抗原，OV和抗PD-L1联合治疗获益可以恢复。我们的数据通过显示显性抗病毒T细胞应答可以抑制亚显性抗肿瘤T细胞应答,为使用高免疫原性病毒作为肿瘤特异性免疫治疗剂提供了警示信息。然而,通过在病毒中编码肿瘤抗原，溶瘤病毒疗法可以产生抗肿瘤T细胞群体，免疫检查点阻断可以有效地发挥作用。
