The Faculty of Environment and Life, Beijing University of Technology, NO. 100, Pingleyuan, Chaoyang District, Beijing 100124, People's Republic of China.
CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No. 11 Beiyitiao, Zhongguancun, Beijing 100190, People's Republic of China.
Int J Pharm. 2021 Oct 25;608:121091. doi: 10.1016/j.ijpharm.2021.121091. Epub 2021 Sep 20.
Cancer vaccines targeting tumor specific neoantigens derived from nonsynonymous mutations of tumor cells have emerged as an effective approach to induce antitumor T cells responses for personalized cancer immunotherapy. Despite the enormous potential of synthetic peptides as a common modality for neoantigen vaccines, their practical efficacy was limited due to their relatively low immunogenicity. Herein, we modify neoantigen peptide (Adpgk) derived from MC-38 colon carcinoma by supplementing ten consecutive positively-charged lysines (10 K-Adpgk) to obtain cationic polypeptide. And then we made them self-assemble with toll-like receptor 9 (TLR-9) agonist CpG oligodeoxynucleotides (CpG ODN) adjuvant directly forming antigen/adjuvant integrated nanocomplexes (PCNPs) through electrostatic interaction for potent tumor immunotherapy. The optimal formed PCNPs were around 175 nm with uniform size distribution and could maintain stability in physiological saline solution. CpG ODN and 10 K-Adpgk in the formed PCNPs could be effectively uptake by dendritic cells (DCs) and stimulate the maturation of DCs as well as improving the efficiency of antigen cross-presentation efficiency in vitro. Furthermore, the PCNPs vaccine could markedly improve neoantigen and adjuvant co-delivery efficiency to lymphoid organs and activate cytotoxic T cells. In addition, vaccination with PCNPs could not only offer prophylactic to protect mice from challenged MC-38 colorectal tumors, but also achieve a better anti-tumor effect in an established colorectal tumor model, and significantly prolong the survival rate of tumor-bearing mice. Therefore, this work provided a versatile but effective method for neoantigen peptide and CpG ODN co-assembly vaccine platform for efficient colorectal cancer immunotherapy.
针对肿瘤细胞非同义突变衍生的肿瘤特异性新生抗原的癌症疫苗已成为诱导抗肿瘤 T 细胞反应的有效方法，用于个性化癌症免疫治疗。尽管合成肽作为新抗原疫苗的一种常见模式具有巨大的潜力，但由于其相对较低的免疫原性，其实际疗效受到限制。在此，我们通过在源自 MC-38 结肠癌细胞的新生抗原肽（Adpgk）上修饰 10 个连续的正电荷赖氨酸（10K-Adpgk），获得阳离子多肽。然后，我们通过静电相互作用直接将它们与 Toll 样受体 9（TLR-9）激动剂 CpG 寡脱氧核苷酸（CpG ODN）佐剂自组装，形成抗原/佐剂整合纳米复合物（PCNPs），用于有效的肿瘤免疫治疗。最佳形成的 PCNPs 约为 175nm，具有均匀的粒径分布，并能在生理盐水中保持稳定。CpG ODN 和形成的 PCNPs 中的 10K-Adpgk 可以被树突状细胞（DCs）有效摄取，并刺激 DCs 的成熟，提高抗原交叉呈递效率。此外，PCNPs 疫苗可以显著提高新生抗原和佐剂向淋巴器官的共递药效率，激活细胞毒性 T 细胞。此外，接种 PCNPs 不仅可以提供预防措施，保护小鼠免受 MC-38 结直肠肿瘤的挑战，而且可以在已建立的结直肠肿瘤模型中实现更好的抗肿瘤效果，并显著延长荷瘤小鼠的存活率。因此，这项工作为新型抗原肽和 CpG ODN 共组装疫苗平台提供了一种通用而有效的方法，用于高效的结直肠癌免疫治疗。
