Cancer vaccines, which activate the immune system against a target antigen, are attractive for prostate cancer, where multiple upregulated protein targets are identified. However, many clinical trials implementing peptides targeting these proteins have yielded suboptimal results. Using spherical nucleic acids (SNAs), we explore how precise architectural control of vaccine components can activate a robust antigen-specific immune response in comparison to clinical formulations of the same targets. The SNA vaccines incorporate peptides for human prostate-specific membrane antigen (PSMA) or T-cell receptor γ alternate reading frame protein (TARP) into an optimized architecture, resulting in high rates of immune activation and cytolytic ability in humanized mice and human peripheral blood mononuclear cells (hPBMCs). Specifically, administered SNAs elevate the production and secretion of cytokines and increase polyfunctional cytotoxic T cells and effector memory. Importantly, T cells raised from immunized mice potently kill targets, including clinically relevant cells expressing the whole PSMA protein. Treatment of hPBMCs increases costimulatory markers and cytolytically active T cells. This work demonstrates the importance of vaccine structure and its ability to reformulate and elevate clinical targets. Moreover, it encourages the field to reinvestigate ineffective peptide targets and repackage them into optimally structured vaccines to harness antigen potency and enhance clinical outcomes.

中文翻译：

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球形核酸疫苗结构显着影响临床使用的前列腺癌靶标的适应性免疫反应

癌症疫苗可以激活针对目标抗原的免疫系统，对前列腺癌很有吸引力，因为在前列腺癌中发现了多个上调的蛋白质目标。然而，许多针对这些蛋白质的肽的临床试验取得了次优的结果。使用球形核酸（SNA），我们探索了与相同靶标的临床制剂相比，疫苗成分的精确结构控制如何激活强大的抗原特异性免疫反应。SNA 疫苗将人前列腺特异性膜抗原 (PSMA) 或 T 细胞受体γ替代阅读框蛋白 (TARP) 的肽纳入优化的结构中，从而在人源化小鼠和人外周血中产生高免疫激活率和细胞溶解能力单核细胞（hPBMC）。具体来说，施用 SNA 可以提高细胞因子的产生和分泌，并增加多功能细胞毒性 T 细胞和效应记忆。重要的是，从免疫小鼠中产生的 T 细胞可以有效杀死靶标，包括表达整个 PSMA 蛋白的临床相关细胞。hPBMC 的治疗会增加共刺激标记物和细胞溶解活性 T 细胞。这项工作证明了疫苗结构的重要性及其重新制定和提升临床目标的能力。此外，它鼓励该领域重新研究无效的肽靶标，并将其重新包装成结构最佳的疫苗，以利用抗原效力并增强临床结果。