Wan Zhuoya, Huang Haozhe, West Raymond E, Zhang Min, Zhang Bei, Cai Xinran, Zhang Ziqian, Luo Zhangyi, Chen Yuang, Zhang Yue, Xie Wen, Yang Da, Nolin Thomas D, Wang Junmei, Li Song, Sun Jingjing
Center for Pharmacogenetics, Department of Pharmaceutical Science, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.
Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.
Mater Today (Kidlington). 2023 Jan-Feb;62:33-50. doi: 10.1016/j.mattod.2022.11.008. Epub 2022 Dec 8.
STING agonist has recently gained much attention for cancer treatment, but the therapeutic potential of STING agonist is hampered by STING-associated tumor immune resistance. In this work, guided by both bioinformatics and computer modeling, we rationally designed a "one stone hits two birds" nanoparticle-based strategy to simultaneously activate STING innate immune response while eliminating STING-associated immune resistance for the treatment of pancreatic ductal adenocarcinoma (PDAC). We discovered that the ultra-small sized micellar system based on gemcitabine-conjugated polymer (PGEM), which showed superior capacity of penetration in pancreatic tumor spheroid model and orthotopic tumor model, could serve as a novel "STING agonist". The activation of STING signaling in dendritic cells (DCs) by PGEM increased both innate nature killer (NK) and adaptive anti-tumor T cell response. However, activation of STING signaling by PGEM in tumor cells also drove the induction of chemokines CCL2 and CCL7, resulting in immune resistance by recruiting tumor associated macrophage (TAM) and myeloid-derived suppressor cells (MDSCs). Through the combination of computer modeling and experimental screening, we developed a dual delivery modality by incorporating a CCR2 (the receptor shared by both CCL2 and CCL7) antagonist PF-6309 (PF) into PGEM micellar system. Our studies demonstrated that PGEM/PF formulation significantly reduced pancreatic tumor burden and induced potent anti-tumor immunity through reversing the CCL2/CCL7-mediated immunosuppression. Moreover, PGEM/PF sensitized PDAC tumors to anti-PD-1 therapy, leading to complete suppression/eradication of the tumors. Our work has shed light to the multi-faceted role of STING activation and provided a novel immunotherapy regimen to maximize the benefit of STING activation for PDAC treatment. In addition, this work paved a new way for bioinformatics and computer modeling-guided rational design of nanomedicine.
STING激动剂最近在癌症治疗方面备受关注，但其治疗潜力受到与STING相关的肿瘤免疫抗性的阻碍。在这项工作中，在生物信息学和计算机建模的指导下，我们合理设计了一种基于纳米颗粒的“一石二鸟”策略，在治疗胰腺导管腺癌（PDAC）时同时激活STING先天免疫反应，同时消除与STING相关的免疫抗性。我们发现，基于吉西他滨共轭聚合物（PGEM）的超小尺寸胶束系统在胰腺肿瘤球体模型和原位肿瘤模型中显示出卓越的渗透能力，可作为一种新型的“STING激动剂”。PGEM对树突状细胞（DCs）中STING信号的激活增强了先天自然杀伤（NK）细胞和适应性抗肿瘤T细胞反应。然而，PGEM在肿瘤细胞中激活STING信号也会促使趋化因子CCL2和CCL7的诱导，通过招募肿瘤相关巨噬细胞（TAM）和髓系来源的抑制细胞（MDSC）导致免疫抗性。通过计算机建模和实验筛选相结合，我们通过将CCR2（CCL2和CCL7共同的受体）拮抗剂PF-6309（PF）纳入PGEM胶束系统开发了一种双重递送方式。我们的研究表明，PGEM/PF制剂通过逆转CCL2/CCL7介导的免疫抑制作用，显著减轻了胰腺肿瘤负担并诱导了强大的抗肿瘤免疫力。此外，PGEM/PF使PDAC肿瘤对抗PD-1治疗敏感，导致肿瘤完全抑制/根除。我们的工作揭示了STING激活的多方面作用，并提供了一种新型免疫治疗方案，以最大限度地提高STING激活对PDAC治疗的益处。此外，这项工作为生物信息学和计算机建模指导的纳米药物合理设计开辟了一条新途径。
