Sisi Liu1, Mingxin Li2, Fengqiao Sun3, Junwen Zhang4, Fusheng Liu5. 1. Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Dongjiao Minxiang 1, Dongcheng District, Beijing, 100730, China. 2. 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. 3. Department of Neurosurgery, Peking University International Hospital, Peking University Health Science Center, Peking University, Shengming Kexueyuan 1, Changping District, Beijing, 102206, China. 4. 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. jewzhang@hotmail.com. 5. 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. liufushengs@hotmail.com.
Abstract
PURPOSE: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.
PURPOSE: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.
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