Center for Translational Oncology and Immunology (TRON), Mainz, Germany.
Cancer Res. 2010 Nov 15;70(22):9031-40. doi: 10.1158/0008-5472.CAN-10-0699. Epub 2010 Nov 2.
Although naked antigen-encoding RNA has entered clinical testing, basic knowledge on how to apply this promising novel vaccine format is still pending. By comparing different administration routes, we observed surprisingly potent antigen-specific T-cell immunity upon intranodal injection of naked antigen-encoding RNA. RNA was selectively uptaken by resident dendritic cells, propagated a T-cell attracting and stimulatory intralymphatic milieu, and led to efficient expansion of antigen-specific CD8+ as well as CD4+ T cells. By intranodal treatment of mice with repeated cycles of RNA, we achieved de novo priming of naïve T cells, which became potent cytolytic effectors capable of homing to primary and secondary lymphatic tissues as well as memory T cells. In tumor-bearing mice intralymphatic RNA vaccination elicited protective and therapeutic antitumor immune responses, resulting in a remarkable survival benefit as compared with other treatment regimens. This is the first report of strong systemic antigen-specific Th1-type immunity and cancer cure achieved with naked antigen-encoding RNA in preclinical animal models.
尽管裸抗原编码 RNA 已进入临床测试，但如何应用这种有前途的新型疫苗形式的基本知识仍有待研究。通过比较不同的给药途径，我们观察到在淋巴结内注射裸抗原编码 RNA 时会产生令人惊讶的强效抗原特异性 T 细胞免疫。RNA 被驻留的树突状细胞选择性摄取，增殖出吸引和刺激 T 细胞的淋巴管内环境，并导致抗原特异性 CD8+和 CD4+T 细胞的有效扩增。通过用 RNA 对小鼠进行重复的淋巴结内治疗，我们实现了对幼稚 T 细胞的从头诱导，这些细胞成为有效的细胞毒性效应物，能够归巢到初级和次级淋巴组织以及记忆 T 细胞。在荷瘤小鼠中，淋巴管内 RNA 疫苗接种引发了保护性和治疗性的抗肿瘤免疫反应，与其他治疗方案相比，显著提高了生存率。这是在临床前动物模型中使用裸抗原编码 RNA 实现强烈的全身抗原特异性 Th1 型免疫和癌症治愈的首例报道。
