Bhatt Darshak K, Meuleman Saskia L, Hoogeboom Baukje Nynke, Daemen Toos
Department of Medical Microbiology and Infection Prevention, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, the Netherlands.
iScience. 2024 Feb 16;27(3):109253. doi: 10.1016/j.isci.2024.109253. eCollection 2024 Mar 15.
Oncolytic viruses show promise in enhancing tumor immunogenicity by releasing immunogenic signals during tumor cell infection and lysis. In this study, we improved the virus-induced tumor immunogenicity of recombinant Semliki Forest virus (rSFV)-based replicon particles by encoding immunogenic cytokines such as C-X-C motif chemokine ligand 10 (CXCL10), FMS-like tyrosine kinase 3 ligand (Flt3L), or interferon-gamma (IFN-ƴ). Real-time imaging and flow cytometry of human cancer cell-based monolayer and spheroid cultures, using LNCaP or PANC-1 cells, revealed effective infection and transgene expression in both models. LNCaP cells exhibited higher and earlier rSFV infection compared to PANC-1 cells. While infected LNCaP cells effectively triggered immune recruitment and T cell activation even without encoding cytokines, PANC-1 cells demonstrated improved immune responses only when infected with replicons encoding cytokines, particularly IFN-ƴ, which enhanced tumor immunogenicity irrespective of cancer cell susceptibility to infection. Our study demonstrates that despite innate phenotypic disparities in cancer cells, rSFV-based replicons encoding cytokines can potentially generate effective immune responses in the tumor.
溶瘤病毒在通过肿瘤细胞感染和裂解过程中释放免疫原性信号来增强肿瘤免疫原性方面显示出前景。在本研究中，我们通过编码免疫原性细胞因子，如C-X-C基序趋化因子配体10（CXCL10）、FMS样酪氨酸激酶3配体（Flt3L）或干扰素-γ（IFN-ƴ），提高了基于重组塞姆利基森林病毒（rSFV）的复制子颗粒的病毒诱导肿瘤免疫原性。使用LNCaP或PANC-1细胞对基于人癌细胞的单层和球体培养物进行实时成像和流式细胞术分析，发现在两种模型中均有有效的感染和转基因表达。与PANC-1细胞相比，LNCaP细胞表现出更高且更早的rSFV感染。虽然即使不编码细胞因子，被感染的LNCaP细胞也能有效触发免疫募集和T细胞活化，但PANC-1细胞只有在感染编码细胞因子的复制子时才表现出改善的免疫反应，特别是IFN-ƴ，它增强了肿瘤免疫原性，而与癌细胞对感染的敏感性无关。我们的研究表明，尽管癌细胞存在先天性表型差异，但编码细胞因子的基于rSFV的复制子可能在肿瘤中产生有效的免疫反应。
