It is a daunting therapeutic challenge to completely eradicate hepatocellular carcinoma (HCC) from patients. Alpha-fetoprotein (AFP) -based vaccines appear promising, however the efficacy needs to be improved. Methods: Here, we explore if fusing high-mobility group nucleosome binding protein 1 (HMGN1), a potent immunoadjuvant, to AFP (lenti-HA) can augment the antitumor immunity of AFP-expressing lentiviral vector (lenti-AFP), a vehicle extensively employed for genetic immunization with high transduction efficacy and good safety profiles. The antitumor immunity of Lenti-HA was systemically assessed in ectopic, orthotopic and autochthonous HCC models. Results: Lenti-HA elicited strong anti-HCC effects in mice and amplified the antitumor immunity of lenti-AFP by reducing effective dose 6-fold. Importantly, lenti-HA induced a robust antitumor immune response with prolonged survival rate and improved the immune and tumor microenvironment in mice with carcinogen-induced autochthonous HCC. Lenti-HA localized primarily to lymphoid organs with no preference for specific immune cell types. Activated dendritic cells (DCs), particularly CD103+CD11b- DCs, were also actively recruited to lymph nodes in lenti-HA-treated HCC mice. Moreover, lenti-HA-transduced human DCs elicited stronger immune response than lenti-AFP against HCC cells in vitro. Conclusion: Our study demonstrates that HMGN1 augments the antitumor immunity of AFP-expressing lentiviral vaccines in HCC mice and human cells in vitro and thus provides a new therapeutic strategy for HCC.

中文翻译：

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Alarmin 增强慢病毒疫苗对异位、原位和原位肝细胞癌小鼠的抗肿瘤免疫力。


从患者身上彻底根除肝细胞癌（HCC）是一项艰巨的治疗挑战。基于甲胎蛋白（AFP）的疫苗似乎很有前景，但功效有待提高。方法：在这里，我们探讨将高迁移率基团核小体结合蛋白 1 (HMGN1)（一种有效的免疫佐剂）与 AFP (lenti-HA) 融合是否可以增强表达 AFP 的慢病毒载体 (lenti-AFP)（一种载体）的抗肿瘤免疫力广泛用于基因免疫，具有高转导效率和良好的安全性。在异位、原位和原位 HCC 模型中系统评估了 Lenti-HA 的抗肿瘤免疫力。结果：Lenti-HA 在小鼠体内产生了强烈的抗 HCC 作用，并通过将有效剂量降低 6 倍，增强了 Lenti-AFP 的抗肿瘤免疫力。重要的是，lenti-HA 诱导了强大的抗肿瘤免疫反应，延长了存活率，并改善了致癌物诱导的原发性 HCC 小鼠的免疫和肿瘤微环境。 Lenti-HA 主要定位于淋巴器官，对特定免疫细胞类型没有偏好。在慢病毒HA治疗的HCC小鼠中，活化的树突状细胞（DC），特别是CD103+CD11b-DC，也被积极地募集至淋巴结。此外，在体外，慢病毒HA转导的人类树突状细胞比慢病毒AFP更能引发针对HCC细胞的更强的免疫反应。结论：我们的研究表明，HMGN1 在体外增强了表达 AFP 的慢病毒疫苗在 HCC 小鼠和人类细胞中的抗肿瘤免疫力，从而为 HCC 提供了新的治疗策略。