Overcoming pancreatic cancer immune resistance by codelivery of CCR2 antagonist using a STING-activating gemcitabine-based nanocarrier.
Overcoming pancreatic cancer immune resistance by codelivery of CCR2 antagonist using a STING-activating gemcitabine-based nanocarrier.
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DOI：
10.1016/j.mattod.2022.11.008
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发表时间：
2022-12
期刊：
影响因子：
24.2
通讯作者：
Zhuoya Wan;Haozhe Huang;Raymond E. West III;M. Zhang;Bei Zhang;Xinran Cai;Ziqian Zhang;Zhangyi Luo;Yuang Chen;Yue Zhang;Wen Xie;D. Yang;T. Nolin;Junmei Wang;Song Li;Jingjing Sun
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文献类型：
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作者：
Zhuoya Wan;Haozhe Huang;Raymond E. West III;M. Zhang;Bei Zhang;Xinran Cai;Ziqian Zhang;Zhangyi Luo;Yuang Chen;Yue Zhang;Wen Xie;D. Yang;T. Nolin;Junmei Wang;Song Li;Jingjing Sun
近年来，STING激动剂在肿瘤治疗中受到广泛关注，但由于STING相关的肿瘤免疫抵抗，STING激动剂的治疗潜力受到阻碍。在生物信息学和计算机模拟的指导下，我们合理地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)的同时激活STING先天免疫反应，同时消除STING相关的免疫抵抗。我们发现，基于吉西他滨共轭聚合物(PGEM)的超小型胶束体系在胰腺肿瘤球体模型和原位肿瘤模型中表现出了良好的穿透能力，可以作为一种新型的“刺激剂”。PGEM激活树突状细胞(DC)上的STING信号可增强天然杀伤细胞(NK)和适应性抗肿瘤T细胞应答。然而，PGEM激活肿瘤细胞中的STING信号也促使趋化因子CCL2和CCL7的诱导，通过募集肿瘤相关巨噬细胞()和髓系来源的抑制细胞(MDSCs)而导致免疫耐受。通过计算机模拟和实验筛选相结合的方法，我们将CCR2(CCL2和CCL7共有的受体)拮抗剂PF-6309(PF)引入到PGEM胶束系统中，开发了一种双重给药方式。我们的研究表明，PGEM/PF制剂通过逆转CCL2/CCL7介导的免疫抑制，显著降低胰腺肿瘤的负担，并诱导强大的抗肿瘤免疫。此外，PGEM/PF使PDAC肿瘤对抗PD-1治疗增敏，导致肿瘤的完全抑制/根除。我们的工作揭示了STING激活的多方面作用，并为PDAC治疗提供了一种新的免疫治疗方案，使STING激活的益处最大化。此外，这项工作还为生物信息学和计算机建模指导纳米药物的合理设计开辟了一条新的途径。
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.