The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, P. R. China.
Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, People's Republic of China.
Theranostics. 2023 Jul 16;13(12):4166-4181. doi: 10.7150/thno.85843. eCollection 2023.
Although neoantigen-based cancer vaccines have shown promise in various solid tumors, limited immune responses and clinical outcomes have been reported in patients with advanced disease. Cytosolic transport of neoantigen and adjuvant is required for the activation of intracellular Toll-like receptors (TLRs) and cross-presentation to prime neoantigen-specific CD8T cells but remains a significant challenge. In this study, we aimed to develop a virus-like silicon vaccine (V-scVLPs) with a unique spike topological structure, capable of efficiently co-delivering a hepatocellular carcinoma (HCC)-specific neoantigen and a TLR9 agonist to dendritic cells (DCs) to induce a robust CD8T cell response to prevent orthotopic tumor growth. We evaluated the antitumor efficacy of V-scVLPs by examining tumor growth and survival time in animal models, as well as analyzing tumor-infiltrating CD8T cells and cytokine responses in the tumor microenvironment (TME). To evaluate the synergistic efficacy of V-scVLPs in combination with α-TIM-3 in HCC, we used an orthotopic HCC mouse model, a lung metastasis model, and a tumor rechallenge model after hepatectomy. We found that V-scVLPs can efficiently co-deliver the hepatocellular carcinoma (HCC)-specific neoantigen and the TLR9 agonist to DCs caveolin-mediated endocytosis. This advanced delivery strategy results in efficient lymph node draining of V-scVLPs to activate lymphoid DC maturation for promoting robust CD8T cells and central memory T cells responses, which effectively prevents orthotopic HCC tumor growth. However, in the established orthotopic liver tumor models, the inhibitory receptor of TIM-3 was significantly upregulated in tumor-infiltrating CD8T cells after immunization with V-scVLPs. Blocking the TIM-3 signaling further restored the antitumor activity of V-scVLPs-induced CD8T cells, reduced the proportion of regulatory T cells, and increased the levels of cytokines to alter the tumor microenvironment to efficiently suppress established orthotopic HCC tumor growth, and inhibit lung metastasis as well as recurrence after hepatectomy. Overall, the developed novel spike nanoparticles with efficient neoantigen and adjuvant intracellular delivery capability holds great promise for future clinical translation to improve HCC immunotherapy.
虽然基于新抗原的癌症疫苗在各种实体瘤中显示出了前景，但在晚期疾病患者中，免疫反应和临床结果有限。新抗原和佐剂的细胞质转运对于激活细胞内 Toll 样受体 (TLR) 和交叉呈递以启动新抗原特异性 CD8T 细胞是必要的，但仍然是一个重大挑战。在这项研究中，我们旨在开发一种具有独特刺突拓扑结构的病毒样硅疫苗 (V-scVLPs)，能够有效地共递呈肝细胞癌 (HCC) 特异性新抗原和 TLR9 激动剂给树突状细胞 (DC)，以诱导强大的 CD8T 细胞反应，防止原位肿瘤生长。我们通过检查动物模型中的肿瘤生长和生存时间，以及分析肿瘤微环境 (TME) 中的肿瘤浸润性 CD8T 细胞和细胞因子反应，来评估 V-scVLPs 的抗肿瘤疗效。为了评估 V-scVLPs 与 α-TIM-3 联合在 HCC 中的协同疗效，我们使用了原位 HCC 小鼠模型、肺转移模型和肝切除后肿瘤再挑战模型。我们发现，V-scVLPs 可以通过 caveolin 介导的内吞作用有效地共递呈肝细胞癌 (HCC) 特异性新抗原和 TLR9 激动剂给 DC。这种先进的递药策略导致 V-scVLPs 有效地引流到淋巴结，激活淋巴样 DC 成熟，促进强大的 CD8T 细胞和中央记忆 T 细胞反应，有效地防止原位 HCC 肿瘤生长。然而，在已建立的原位肝肿瘤模型中，在免疫接种 V-scVLPs 后，肿瘤浸润性 CD8T 细胞中 TIM-3 的抑制受体显著上调。阻断 TIM-3 信号进一步恢复了 V-scVLPs 诱导的 CD8T 细胞的抗肿瘤活性，降低了调节性 T 细胞的比例，并增加了细胞因子的水平，改变了肿瘤微环境，有效地抑制了已建立的原位 HCC 肿瘤生长，并抑制了肺转移以及肝切除后的复发。总体而言，具有高效新抗原和佐剂细胞内递药能力的新型刺突纳米颗粒具有很大的临床转化潜力，可改善 HCC 免疫治疗。
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