Abstract：
Cancer vaccines aim at generating cytotoxic CD8+ T cells that kill cancer cells and confer durable tumor regression. Hereto, CD8+ peptide epitopes should be presented by antigen presenting cells to CD8+ T cells in lymphoid tissue. Unfortunately, in unformulated soluble form, peptide antigens are poorly taken up by antigen presenting cells and do not efficiently reach lymph nodes. Hence, the lack of efficient delivery remains a major limitation for successful clinical translation of cancer vaccination using peptide antigens. Here we propose a generic peptide nanoformulation strategy by extending the amino acid sequence of the peptide antigen epitope with 10 glutamic acid residues. The resulting overall anionic charge of the peptide allows encapsulation into lipid nanoparticles (peptide-LNP) by electrostatic interaction with an ionizable cationic lipid. We demonstrate that intravenous injection of peptide-LNP efficiently delivers the peptide to immune cells in the spleen. Peptide-LNP that co-encapsulate an imidazoquinoline TLR7/8 agonist (IMDQ) induce robust innate immune activation in a broad range of immune cell subsets in the spleen. Peptide-LNP containing the minimal CD8+ T cell epitope of the HPV type 16 E7 oncoprotein and IMDQ induces high levels of antigen-specific CD8+ T cells in the blood, and can confer protective immunity against E7-expressing tumors in both prophylactic and therapeutic settings.
摘要：
癌症疫苗旨在产生杀死癌细胞并赋予持久肿瘤消退的细胞毒性CD8+T细胞。在此，CD8+肽表位应由抗原呈递细胞呈递至淋巴组织中的CD8+T细胞。不幸的是,以未配制的可溶形式，肽抗原很少被抗原呈递细胞吸收，不能有效地到达淋巴结。因此，缺乏有效的递送仍然是使用肽抗原成功临床转化癌症疫苗的主要限制.在这里，我们提出了一种通用的肽纳米制剂策略，通过用10个谷氨酸残基扩展肽抗原表位的氨基酸序列。所得到的肽的总阴离子电荷允许通过与可电离的阳离子脂质的静电相互作用封装到脂质纳米颗粒(肽-LNP)中。我们证明了肽-LNP的静脉内注射有效地将肽递送至脾脏中的免疫细胞。共包封咪唑喹啉TLR7/8激动剂(IMDQ)的肽-LNP在脾脏中的宽范围的免疫细胞亚群中诱导稳健的先天性免疫活化。含有HPV16型E7癌蛋白和IMDQ的最小CD8+T细胞表位的肽-LNP诱导血液中高水平的抗原特异性CD8+T细胞,并且可以在预防和治疗环境中赋予针对表达E7的肿瘤的保护性免疫。
