Xie Daping, Han Congwei, Chen Chonghao, Liao Zhencheng, Campos de Souza Senio, Niu Yiming, Mano João F, Dong Lei, Wang Chunming
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau SAR, China.
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China.
Bioact Mater. 2024 Apr 23;37:315-330. doi: 10.1016/j.bioactmat.2024.03.035. eCollection 2024 Jul.
Cancer vaccination holds great promise for cancer treatment, but its effectiveness is hindered by suboptimal activation of CD8 cytotoxic T lymphocytes, which are potent effectors to mediate anti-tumor immune responses. A possible solution is to switch antigen-presenting cells to present tumor antigens the major histocompatibility complex class I (MHC-I) to CD8 T cells - a process known as cross-presentation. To achieve this goal, we develop a three-dimensional (3D) scaffold vaccine to promote antigen cross-presentation by persisted toll-like receptor-2 (TLR2) activation after one injection. This vaccine comprises polysaccharide frameworks that "hook" TLR2 agonist (acGM) tunable hydrophobic interactions and forms a 3D macroporous scaffold click chemistry upon subcutaneous injection. Its retention-and-release of acGM enables sustained TLR2 activation in abundantly recruited dendritic cells , inducing intracellular production of reactive oxygen species (ROS) in optimal kinetics that crucially promotes efficient antigen cross-presentation. The scaffold loaded with model antigen ovalbumin (OVA) or tumor specific antigen can generate potent immune responses against lung metastasis in B16-OVA-innoculated wild-type mice or spontaneous colorectal cancer in transgenic Apc mice, respectively. Notably, it requires neither additional adjuvants nor external stimulation to function and can be adjusted to accommodate different antigens. The developed scaffold vaccine may represent a new, competent tool for next-generation personalized cancer vaccination.
癌症疫苗接种对癌症治疗具有巨大潜力，但其有效性受到CD8细胞毒性T淋巴细胞激活不足的阻碍，而CD8细胞毒性T淋巴细胞是介导抗肿瘤免疫反应的有效效应细胞。一种可能的解决方案是将抗原呈递细胞转变为向CD8 T细胞呈递主要组织相容性复合体I类（MHC-I）的肿瘤抗原，这一过程称为交叉呈递。为实现这一目标，我们开发了一种三维（3D）支架疫苗，通过单次注射后持续激活Toll样受体2（TLR2）来促进抗原交叉呈递。这种疫苗包含多糖框架，该框架通过可调疏水相互作用“钩住”TLR2激动剂（acGM），并在皮下注射时通过点击化学形成3D大孔支架。其对acGM的保留和释放能够在大量募集的树突状细胞中持续激活TLR2，以最佳动力学诱导细胞内活性氧（ROS）的产生，这对有效促进抗原交叉呈递至关重要。负载模型抗原卵清蛋白（OVA）或肿瘤特异性抗原的支架分别可以在接种B16-OVA的野生型小鼠中产生针对肺转移的强效免疫反应，或在转基因Apc小鼠中产生针对自发性结直肠癌的强效免疫反应。值得注意的是，它既不需要额外的佐剂也不需要外部刺激就能发挥作用，并且可以进行调整以适应不同的抗原。所开发的支架疫苗可能代表了一种用于下一代个性化癌症疫苗接种的新型有效工具。
