The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics and Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) and School of Medical Technology and School of Basic Medical Sciences, Tianjin Medical University, Qixiangtai Road, Heping District, Tianjin, 300070, China.
Department of Nanomedicine and Biopharmaceuticals, National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan, 430074, Hubei Province, China.
J Hematol Oncol. 2022 Apr 29;15(1):46. doi: 10.1186/s13045-022-01266-8.
Personalized immunotherapy utilizing cancer vaccines tailored to the tumors of individual patients holds promise for tumors with high genetic heterogeneity, potentially enabling eradication of the tumor in its entirety.
Here, we demonstrate a general strategy for biological nanovaccines that trigger tailored tumor-specific immune responses for hepatocellular carcinoma (HCC). Dendritic cell (DC)-derived exosomes (DEX) are painted with a HCC-targeting peptide (P47-P), an α-fetoprotein epitope (AFP212-A2) and a functional domain of high mobility group nucleosome-binding protein 1 (N1ND-N), an immunoadjuvant for DC recruitment and activation, via an exosomal anchor peptide to form a "trigger" DEX vaccine (DEX).
DEX specifically promoted recruitment, accumulation and activation of DCs in mice with orthotopic HCC tumor, resulting in enhanced cross-presentation of tumor neoantigens and de novo T cell response. DEX elicited significant tumor retardation and tumor-specific immune responses in HCC mice with large tumor burdens. Importantly, tumor eradication was achieved in orthotopic HCC mice when antigenic AFP peptide was replaced with the full-length AFP (A) to form DEX. Supplementation of Fms-related tyrosine kinase 3 ligand greatly augmented the antitumor immunity of DEX by increasing immunological memory against tumor re-challenge in orthotopic HCC mice. Depletion of T cells, cross-presenting DCs and other innate immune cells abrogated the functionality of DEX.
These findings demonstrate the capacity of universal DEX vaccines to induce tumor-specific immune responses by triggering an immune response tailored to the tumors of each individual, thus presenting a generalizable approach for personalized immunotherapy of HCC, by extension of other tumors, without the need to identify tumor antigens.
利用针对个体患者肿瘤的个体化免疫疗法利用癌症疫苗具有很大的潜力，对于遗传异质性高的肿瘤，有可能实现完全消除肿瘤。
在这里，我们展示了一种针对肝细胞癌（HCC）的通用生物纳米疫苗策略。通过外泌体锚定肽将 HCC 靶向肽（P47-P）、甲胎蛋白表位（AFP212-A2）和高迁移率族核小体结合蛋白 1 的功能域（N1ND-N），一种用于树突状细胞（DC）募集和激活的免疫佐剂，涂在外泌体衍生的外泌体（DEX）上，形成“触发”DEX 疫苗（DEX）。
DEX 特异性地促进了荷瘤小鼠中同源 HCC 肿瘤中 DC 的募集、积累和激活，导致肿瘤新抗原的交叉呈递和新 T 细胞反应增强。DEX 在具有大肿瘤负荷的 HCC 小鼠中引起了明显的肿瘤延迟和肿瘤特异性免疫反应。重要的是，当用全长 AFP（A）替代抗原性 AFP 肽时，DEX 在荷瘤 HCC 小鼠中实现了肿瘤的根除。补充 Fms 相关酪氨酸激酶 3 配体（Fms-related tyrosine kinase 3 ligand，FLT3L）通过增加对 HCC 小鼠中肿瘤再挑战的免疫记忆，极大地增强了 DEX 的抗肿瘤免疫。耗尽 T 细胞、交叉呈递 DC 和其他固有免疫细胞会破坏 DEX 的功能。
这些发现表明，通用 DEX 疫苗通过触发针对每个个体肿瘤的免疫反应，具有诱导肿瘤特异性免疫反应的能力，从而为 HCC 的个体化免疫治疗提供了一种可推广的方法，也可扩展到其他肿瘤，而无需鉴定肿瘤抗原。
