Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Dongjiao Minxiang 1, Dongcheng District, Beijing, 100730, China.
Brain Tumor Research Center, Beijing Neurosurgical Institute, Beijing Laboratory of Biomedical Materials, Department of Neurosurgery, Beijing Tiantan Hospital affiliated to Capital Medical University, No. 119 Nansihuan West Road, Fengtai District, Beijing, 100070, China.
J Cancer Res Clin Oncol. 2023 Feb;149(2):901-912. doi: 10.1007/s00432-022-04272-y. Epub 2022 Aug 28.
Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults, with patients having a low overall survival rate. Oncolytic viruses (OVs) have been shown effective as monotherapy or combined with immunotherapy in the treatment of UM. Oncolytic herpes simplex type I virus (oHSV-1) was found to alter gene expression and immune function in UMs. We investigated whether a combination treatment would be more effective in treating UM and reactive immune cells.
RNA sequencing analysis were used to identify the effect of oHSV-1 infection in UM cells and protein changes were validated by western blot. Cell viability assays were performed through UM cell lines (MUM2B, 92.1, and MP41) and retinal pigment epithelial cell line (ARPE-19) to identify the efficacy and safety of the combination treatment. Western blot, qRT-PCR, cell viability assay and immunocytochemistry were performed to discover the reactivation of immune cells (U937 and HMC3).
Through RNA sequencing analysis and in vitro molecular biology assays, this study tested the ability of oHSV-1 combined with the TLR3 agonist poly(I:C) to re-activate the TLR3 meditated NF-ƙB signaling pathway and further increase the anti-tumor activity of UM cells and macrophages, including the stimulation of macrophage polarization and proliferation.
These findings indicate that the treatment of UM with a combination of oHSV-1 and poly(I:C) generates immune responses and enhances anti-tumoral activity, suggesting the need for further investigations and clinical trials of this combination.
葡萄膜黑色素瘤（UM）是成人中最常见的原发性眼内恶性肿瘤，患者总体存活率低。溶瘤病毒（OVs）已被证明在治疗 UM 方面作为单一疗法或与免疫疗法联合使用是有效的。单纯疱疹病毒 I 型（oHSV-1）溶瘤病毒已被发现可改变 UMs 的基因表达和免疫功能。我们研究了联合治疗是否会更有效地治疗 UM 和反应性免疫细胞。
采用 RNA 测序分析来鉴定 oHSV-1 感染对 UM 细胞的影响，并通过 Western blot 验证蛋白变化。通过 UM 细胞系（MUM2B、92.1 和 MP41）和视网膜色素上皮细胞系（ARPE-19）进行细胞活力测定，以确定联合治疗的疗效和安全性。通过 Western blot、qRT-PCR、细胞活力测定和免疫细胞化学法来发现免疫细胞（U937 和 HMC3）的再激活。
通过 RNA 测序分析和体外分子生物学检测，本研究测试了 oHSV-1 与 TLR3 激动剂 poly(I:C)联合使用重新激活 TLR3 介导的 NF-ƙB 信号通路的能力，进一步增强了 UM 细胞和巨噬细胞的抗肿瘤活性，包括刺激巨噬细胞极化和增殖。
这些发现表明，用 oHSV-1 和 poly(I:C)联合治疗 UM 可产生免疫反应并增强抗肿瘤活性，表明需要进一步研究和临床试验这种联合治疗。
