Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN 37235, USA; Laboratory of Anaesthesia and Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN 37235, USA.
Biomaterials. 2018 Nov;182:82-91. doi: 10.1016/j.biomaterials.2018.07.052. Epub 2018 Jul 30.
Cancer vaccines targeting patient-specific tumor neoantigens have recently emerged as a promising component of the rapidly expanding immunotherapeutic armamentarium. However, neoantigenic peptides typically elicit weak CD8 T cell responses, and so there is a need for universally applicable vaccine delivery strategies to enhance the immunogenicity of these peptides. Ideally, such vaccines could also be rapidly fabricated using chemically synthesized peptide antigens customized to an individual patient. Here, we describe a strategy for simple and rapid packaging of peptide antigens into pH-responsive nanoparticles with endosomal escape activity. Electrostatically-stabilized polyplex nanoparticles (nanoplexes) can be assembled instantaneously by mixing decalysine-modified antigenic peptides and poly(propylacrylic acid) (pPAA), a polyanion with pH-dependent, membrane destabilizing activity. These nanoplexes increase and prolong antigen uptake and presentation on MHC-I (major histocompatibility complex class I) molecules expressed by dendritic cells, resulting in enhanced activation of CD8 T cells. Using an intranasal immunization route, nanoplex vaccines inhibit formation of lung metastases in a murine melanoma model. Additionally, nanoplex vaccines strongly synergize with the adjuvant α-galactosylceramide (α-GalCer) in stimulating robust CD8 T cell responses, significantly increasing survival time in mice with established melanoma tumors. Collectively, these findings demonstrate that peptide/pPAA nanoplexes offer a facile and versatile platform for enhancing CD8 T cell responses to peptide antigens, with potential to complement ongoing advancements in the development of neoantigen-targeted cancer vaccines.
针对患者特异性肿瘤新生抗原的癌症疫苗最近作为迅速发展的免疫治疗武器库中极具前景的组成部分而出现。然而，新生抗原肽通常引发较弱的 CD8 T 细胞反应，因此需要通用的疫苗传递策略来增强这些肽的免疫原性。理想情况下，这些疫苗还可以使用针对个体患者定制的化学合成肽抗原快速制造。在这里，我们描述了一种将肽抗原简单快速包装到具有内体逃逸活性的 pH 响应性纳米颗粒中的策略。通过混合 decalysine 修饰的抗原肽和聚（丙基丙烯酸）（pPAA），可以瞬时组装带正电的多聚物纳米颗粒（nanoplexes），pPAA 是一种具有 pH 依赖性、破坏膜活性的多阴离子。这些纳米颗粒增加并延长了树突状细胞上 MHC-I（主要组织相容性复合体 I 类）分子表达的抗原摄取和呈递，从而增强了 CD8 T 细胞的激活。通过鼻内免疫途径，纳米颗粒疫苗抑制了小鼠黑色素瘤模型中肺转移的形成。此外，纳米颗粒疫苗与佐剂 α-半乳糖神经酰胺（α-GalCer）强烈协同刺激强大的 CD8 T 细胞反应，显著增加了患有已建立的黑色素瘤肿瘤的小鼠的存活时间。总的来说，这些发现表明肽/pPAA 纳米颗粒为增强对肽抗原的 CD8 T 细胞反应提供了一种简单而通用的平台，有可能补充针对新生抗原的癌症疫苗的不断发展。
