Xia Xiaojun, Mai Junhua, Xu Rong, Perez Jorge Enrique Tovar, Guevara Maria L, Shen Qi, Mu Chaofeng, Tung Hui-Ying, Corry David B, Evans Scott E, Liu Xuewu, Ferrari Mauro, Zhang Zhiqiang, Li Xian Chang, Wang Rong-Fu, Shen Haifa
Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA.
Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
Cell Rep. 2015 May 12;11(6):957-966. doi: 10.1016/j.celrep.2015.04.009. Epub 2015 Apr 30.
Micro- and nanometer-size particles have become popular candidates for cancer vaccine adjuvants. However, the mechanism by which such particles enhance immune responses remains unclear. Here, we report a porous silicon microparticle (PSM)-based cancer vaccine that greatly enhances cross-presentation and activates type I interferon (IFN-I) response in dendritic cells (DCs). PSM-loaded antigen exhibited prolonged early endosome localization and enhanced cross-presentation through both proteasome- and lysosome-dependent pathways. Phagocytosis of PSM by DCs induced IFN-I responses through a TRIF- and MAVS-dependent pathway. DCs primed with PSM-loaded HER2 antigen produced robust CD8 T cell-dependent anti-tumor immunity in mice bearing HER2+ mammary gland tumors. Importantly, this vaccination activated the tumor immune microenvironment with elevated levels of intra-tumor IFN-I and MHCII expression, abundant CD11c+ DC infiltration, and tumor-specific cytotoxic T cell responses. These findings highlight the potential of PSM as an immune adjuvant to potentiate DC-based cancer immunotherapy.
微米级和纳米级颗粒已成为癌症疫苗佐剂的热门候选物。然而，此类颗粒增强免疫反应的机制仍不清楚。在此，我们报告了一种基于多孔硅微粒（PSM）的癌症疫苗，该疫苗可极大地增强交叉呈递并激活树突状细胞（DC）中的I型干扰素（IFN-I）反应。负载PSM的抗原表现出早期内体定位延长，并通过蛋白酶体和溶酶体依赖性途径增强交叉呈递。DC对PSM的吞噬作用通过TRIF和MAVS依赖性途径诱导IFN-I反应。用负载PSM的HER2抗原致敏的DC在携带HER2+乳腺肿瘤的小鼠中产生了强大的CD8 T细胞依赖性抗肿瘤免疫力。重要的是，这种疫苗接种激活了肿瘤免疫微环境，肿瘤内IFN-I水平升高，MHCII表达增加，CD11c+ DC浸润丰富，以及肿瘤特异性细胞毒性T细胞反应。这些发现突出了PSM作为免疫佐剂增强基于DC的癌症免疫治疗的潜力。
