Department of Chemistry and International Institute for Nanotechnology, Northwestern University, Evanston, IL, USA.
Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA.
Nat Biomed Eng. 2023 Jul;7(7):911-927. doi: 10.1038/s41551-022-01000-2. Epub 2023 Jan 30.
Cancer vaccines must activate multiple immune cell types to be effective against aggressive tumours. Here we report the impact of the structural presentation of two antigenic peptides on immune responses at the transcriptomic, cellular and organismal levels. We used spherical nucleic acid (SNA) nanoparticles to investigate how the spatial distribution and placement of two antigen classes affect antigen processing, cytokine production and the induction of memory. Compared with single-antigen SNAs, a single dual-antigen SNA elicited a 30% increase in antigen-specific T cell activation and a two-fold increase in T cell proliferation. Antigen placement within dual-antigen SNAs altered the gene expression of T cells and tumour growth. Specifically, dual-antigen SNAs encapsulating antigens targeting helper T cells and with externally conjugated antigens targeting cytotoxic T cells elevated antitumour genetic pathways, stalling lymphoma tumours in mice. Additionally, when combined with the checkpoint inhibitor anti-programmed-cell-death protein-1 in a mouse model of melanoma, a specific antigen arrangement within dual-antigen SNAs suppressed tumour growth and increased the levels of circulating memory T cells. The structural design of multi-antigen vaccines substantially impacts their efficacy.
癌症疫苗必须激活多种免疫细胞类型，才能有效对抗侵袭性肿瘤。在这里，我们报告了两种抗原肽的结构呈现方式对转录组、细胞和机体水平免疫反应的影响。我们使用球形核酸 (SNA) 纳米颗粒来研究两种抗原类别的空间分布和位置如何影响抗原处理、细胞因子产生和记忆的诱导。与单一抗原 SNA 相比，单一的双抗原 SNA 可使抗原特异性 T 细胞激活增加 30%，T 细胞增殖增加一倍。双抗原 SNA 内的抗原位置改变了 T 细胞的基因表达和肿瘤生长。具体来说，双抗原 SNA 包裹针对辅助 T 细胞的抗原，外部连接针对细胞毒性 T 细胞的抗原，可提高抗肿瘤基因途径，使小鼠的淋巴瘤肿瘤停滞。此外，在黑色素瘤小鼠模型中与检查点抑制剂抗程序性细胞死亡蛋白-1 联合使用时，双抗原 SNA 内的特定抗原排列抑制肿瘤生长并增加循环记忆 T 细胞的水平。多抗原疫苗的结构设计极大地影响了它们的疗效。
