State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
China State Institute of Pharmaceutical Industry, Shanghai 201203, China.
Nano Lett. 2020 Jun 10;20(6):4393-4402. doi: 10.1021/acs.nanolett.0c01140. Epub 2020 May 29.
Neoantigen-based cancer vaccines are promising for boosting cytotoxic T lymphocyte (CTL) responses. However, the therapeutic effect of cancer vaccines is severely blunted by functional suppression of the dendritic cells (DCs). Herein, we demonstrated an acid-responsive polymeric nanovaccine for activating the stimulator of interferon genes (STING) pathway and improving cancer immunotherapy. The nanovaccines were fabricated by integrating an acid-activatable polymeric conjugate of the STING agonist and neoantigen into one single nanoplatform. The nanovaccines efficiently accumulated at the lymph nodes for promoting DC uptake and facilitating cytosol release of the neoantigens. Meanwhile, the STING agonist activated the STING pathway in the DCs to elicit interferon-β secretion and to boost T-cell priming with the neoantigen. The nanovaccine dramatically inhibited tumor growth and occurrence of B16-OVA melanoma and 4T1 breast tumors in immunocompetent mouse models. Combination immunotherapy with the nanovaccines and anti-PD-L1 antibody demonstrated further improved antitumor efficacy in a 4T1 breast tumor model.
基于新抗原的癌症疫苗在增强细胞毒性 T 淋巴细胞 (CTL) 反应方面很有前景。然而，癌症疫苗的治疗效果受到树突状细胞 (DC) 功能抑制的严重阻碍。在此，我们展示了一种酸响应性聚合物纳米疫苗，用于激活干扰素基因刺激物 (STING) 途径并改善癌症免疫治疗。该纳米疫苗通过将 STING 激动剂和新抗原的酸激活聚合物缀合物整合到单个纳米平台中而构建。纳米疫苗在淋巴结中有效积累，以促进 DC 摄取并促进新抗原的细胞质释放。同时，STING 激动剂激活了 DC 中的 STING 途径，引发干扰素-β的分泌，并增强了新抗原的 T 细胞启动。纳米疫苗在免疫活性小鼠模型中显著抑制了 B16-OVA 黑色素瘤和 4T1 乳腺癌的肿瘤生长和发生。纳米疫苗与抗 PD-L1 抗体联合免疫治疗在 4T1 乳腺癌模型中进一步提高了抗肿瘤疗效。
