Background/Objectives: Oncolytic virotherapy is a promising approach in cancer immunotherapy. We have previously described a recombinant hybrid oncolytic virus (OV), VSV-NDV, which has a favorable safety profile and therapeutic immunogenicity, leading to direct oncolysis, abscopal effects, and prolonged survival in syngeneic in vivo tumor models. While OVs are known to mediate systemic anti-tumor immune responses, the detailed characterization of local and systemic immune responses to fusogenic oncolytic virotherapy remains unexplored. Methods and Results: We analyzed immune cell compartments in the spleen, blood, tumor-draining lymph nodes (TDLNs), and tumors over the course of VSV-NDV therapy in a bilateral syngeneic melanoma mouse model. Our results revealed significant local infiltration and activation of T lymphocytes in tumors and globally in the blood and spleen. Notably, in vivo CD8+T cell depletion led to complete abrogation of the tumor response, highlighting the crucial role of T cells in promoting the therapeutic effects of oncolytic VSV-NDV. In vitro co-culture experiments enabled the interrogation of human immune cell responses to VSV-NDV-mediated oncolysis. Human peripheral blood mononuclear cells (PBMCs) were efficiently stimulated by exposure to VSV-NDV-infected cancer cells, which recapitulates the in vivo murine findings. Conclusions: Taken together, these data characterize a broad anti-tumor immune cell response to oncolytic VSV-NDV therapy and suggest that CD8+T cells play a decisive role in therapeutic outcome, which supports the further development of this chimeric vector as a multimechanistic immunotherapy for solid cancers.
背景/目的：溶瘤病毒疗法是癌症免疫治疗中一种前景广阔的策略。我们先前报道了一种重组杂交溶瘤病毒VSV-NDV，该病毒具有良好的安全性和治疗性免疫原性，能在同基因体内肿瘤模型中引发直接溶瘤效应、远端效应并延长生存期。尽管已知溶瘤病毒可介导系统性抗肿瘤免疫反应，但针对融合型溶瘤病毒疗法引发的局部与全身免疫反应的具体特征尚未明确。方法与结果：我们在双侧同基因黑色素瘤小鼠模型中，系统分析了VSV-NDV治疗过程中脾脏、血液、肿瘤引流淋巴结及肿瘤组织的免疫细胞群变化。研究结果显示，T淋巴细胞在肿瘤局部及全身血液、脾脏中均出现显著浸润与活化。值得注意的是，体内CD8+T细胞耗竭会完全消除肿瘤应答，这凸显了T细胞在促进溶瘤病毒VSV-NDV治疗效果中的关键作用。通过体外共培养实验，我们进一步探究了人类免疫细胞对VSV-NDV介导溶瘤作用的反应。暴露于VSV-NDV感染癌细胞的人外周血单个核细胞被有效激活，该现象重现了小鼠体内实验的发现。结论：本研究系统阐明了溶瘤病毒VSV-NDV疗法引发的广泛抗肿瘤免疫细胞反应，证实CD8+T细胞在治疗结局中起决定性作用，这为将该嵌合载体进一步开发为实体瘤多机制免疫疗法提供了理论依据。
肿瘤(癌症)患者之家