STING 激活剂 c-di-GMP 负载介孔硅纳米颗粒增强乳腺癌免疫治疗。

STING Activator c-di-GMP-Loaded Mesoporous Silica Nanoparticles Enhance Immunotherapy Against Breast Cancer.

机构信息

Graduate Institute of Nanomedicine and Medical Engineering, Taipei Medical University, Taipei 110, Taiwan.

International Ph.D. Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 110, Taiwan.

出版信息

ACS Appl Mater Interfaces. 2020 Dec 23;12(51):56741-56752. doi: 10.1021/acsami.0c16728. Epub 2020 Dec 11.

DOI:10.1021/acsami.0c16728

PMID:33305564

Abstract

Reversing the immunosuppressive tumor microenvironment (TME) is a strategic initiative to sensitize cancer immunotherapy. Emerging evidence shows that cyclic diguanylate monophosphate (c-di-GMP or cdG) can induce the stimulator of interferon genes (STING) pathway activation of antigen-presenting cells (APCs) and upregulate expression of type I interferons (IFNs) to enhance tumor immunogenicity. anionic cdG revealed fast plasma clearance, poor membrane permeability, and inadequate cytosolic bioavailability. Therefore, we explored a comprehensive " vaccination" strategy on the basis of nanomedicine to trigger robust antitumor immunity. Rhodamine B isothiocyanate (RITC) fluorescent mesoporous silica nanoparticles (MSN) synthesized and modified with poly(ethylene glycol) (PEG) and an ammonium-based cationic molecule (TA) were loaded with negatively charged cdG via electrostatic interactions to form cdG@RMSN-PEG-TA. Treatment of RAW 264.7 cells with cdG@RMSN-PEG-TA markedly stimulated the secretion of IL-6, IL-1β, and IFN-β along with phospho-STING (Ser365) protein expression. cdG@RMSN-PEG-TA enhanced infiltration of leukocytes, including CD11c dendritic cells, F4/80 macrophages, CD4 T cells, and CD8 T cells within the tumor microenvironment (TME), resulting in dramatic tumor growth inhibition in 4T1 breast tumor-bearing Balb/c mice. Our findings suggest that a nanobased platform can overcome the obstacles bare cdG can face in the TME. Our approach of an vaccination using a STING agonist provides an attractive immunotherapy-based strategy for treating breast cancer.

摘要

逆转免疫抑制性肿瘤微环境（TME）是使癌症免疫疗法敏感化的一项战略举措。新出现的证据表明，环二鸟苷酸单磷酸（c-di-GMP 或 cdG）可以诱导抗原呈递细胞（APC）中的干扰素基因刺激物（STING）途径的激活，并上调 I 型干扰素（IFNs）的表达，从而增强肿瘤免疫原性。带负电荷的 cdG 显示出快速的血浆清除率、较差的膜通透性和不足的细胞溶质生物利用度。因此，我们探索了一种基于纳米医学的全面“疫苗接种”策略，以引发强大的抗肿瘤免疫。我们合成并修饰了罗丹明 B 异硫氰酸酯（RITC）荧光介孔硅纳米粒子（MSN），使其带有聚乙二醇（PEG）和基于铵的阳离子分子（TA），并通过静电相互作用将带负电荷的 cdG 负载到 cdG@RMSN-PEG-TA 中。用 cdG@RMSN-PEG-TA 处理 RAW 264.7 细胞可显著刺激 IL-6、IL-1β 和 IFN-β 的分泌以及磷酸化 STING（Ser365）蛋白的表达。cdG@RMSN-PEG-TA 增强了白细胞的浸润，包括肿瘤微环境（TME）中的 CD11c 树突状细胞、F4/80 巨噬细胞、CD4 T 细胞和 CD8 T 细胞，从而导致 4T1 乳腺癌荷瘤 Balb/c 小鼠的肿瘤生长显著抑制。我们的研究结果表明，纳米平台可以克服 bare cdG 在 TME 中可能面临的障碍。我们使用 STING 激动剂进行“疫苗接种”的方法为治疗乳腺癌提供了一种有吸引力的基于免疫疗法的策略。