Yao Haochen, Shen Na, Ji Guofeng, Huang Juanjuan, Sun Jiali, Wang Guoqing, Tang Zhaohui, Chen Xuesi
Key Laboratory of Zoonosis Research, Ministry of Education, College of Basic Medical Science, Jilin University, Changchun 130021, P.R. China.
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P.R. China.
Nano Lett. 2022 Apr 27;22(8):3328-3339. doi: 10.1021/acs.nanolett.2c00478. Epub 2022 Apr 11.
Nanomedicines are highly promising for cancer therapy due to their minimal side effects. However, little is known regarding their host immune response, which may limit their clinical efficacy and applications. Here, we find that cisplatin (CDDP)-loaded poly(l-glutamic acid)--methoxy poly(ethylene glycol) complex nanoparticles (CDDP-NPs) elicit a strong antitumor CD8 T cell-mediated immune response in a tumor-bearing mouse model compared to free CDDP. Mechanistically, the sustained retention of CDDP-NPs results in persistent tumor MHC-I overexpression, which promotes the formation of MHC-I-antigen peptide complex (pMHC-I), enhances the interaction between pMHC-I and T cell receptor (TCR), and leads to the activation of TCR signaling pathway and CD8 T cell-mediated immune response. Furthermore, CDDP-NPs upregulate the costimulatory OX40 on intratumoral CD8 T cells, and synergize with the agonistic OX40 antibody (aOX40) to suppress tumor growth by 89.2%. Our study provides a basis for the efficacy advantage of CDDP-based nanomedicines and immunotherapy.
由于副作用极小，纳米药物在癌症治疗方面极具前景。然而，关于其宿主免疫反应的了解却很少，这可能会限制它们的临床疗效和应用。在此，我们发现与游离顺铂相比，负载顺铂（CDDP）的聚（L-谷氨酸）-甲氧基聚（乙二醇）复合纳米颗粒（CDDP-NPs）在荷瘤小鼠模型中引发了强烈的抗肿瘤CD8 T细胞介导的免疫反应。从机制上讲，CDDP-NPs的持续保留导致肿瘤MHC-I持续过表达，这促进了MHC-I-抗原肽复合物（pMHC-I）的形成，增强了pMHC-I与T细胞受体（TCR）之间的相互作用，并导致TCR信号通路的激活和CD8 T细胞介导的免疫反应。此外，CDDP-NPs上调肿瘤内CD8 T细胞上的共刺激分子OX40，并与激动性OX40抗体（aOX40）协同作用，将肿瘤生长抑制了89.2%。我们的研究为基于CDDP的纳米药物的疗效优势和免疫治疗提供了依据。
