A nanoparticle-incorporated STING activator enhances antitumor immunity in PD-L1-insensitive models of triple-negative breast cancer
A nanoparticle-incorporated STING activator enhances antitumor immunity in PD-L1-insensitive models of triple-negative breast cancer
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DOI：
10.1172/jci.insight.120638
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发表时间：
2018-11-15
期刊：
影响因子：
8
通讯作者：
Ting, Jenny P-Y
中科院分区：
文献类型：
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作者：
Cheng, Ning;Watkins-Schulz, Rebekah;Ting, Jenny P-Y
三阴性乳腺癌(TNBC)的治疗选择很少，迫切需要替代治疗方法。干扰素基因刺激物(STING)正在成为治疗佐剂的一个令人兴奋的靶点。然而，STING驻留在细胞内，CDN的细胞内递送，如cGAMP，是STING最佳激活所必需的。我们发现脂质体纳米粒递送的cGAMP(cGAMP-NP)比可溶性cGAMP更有效地激活STING。这些颗粒在原位和基因工程的基底样TNBC模型中诱导针对先前存在的肿瘤的先天和适应性宿主免疫反应。CGAMP-NPs也降低了黑色素瘤的负荷，但对抗PD-L1的反应性有限。在肿瘤微环境中，cGAMP-NPs可引导小鼠和人巨噬细胞(M)从原形成的M2样表型重新编程为M1样表型；增强MHC和共刺激分子的表达；减少M2生物标志物；增加产生干扰素-γ的T细胞；增加肿瘤细胞的凋亡；并增加CD4(+)和CD8(+)T细胞的浸润。激活的T细胞是肿瘤抑制所必需的，因为它们的耗尽会降低抗肿瘤活性。重要的是，cGAMP-NPs可以防止继发性肿瘤的形成，单次剂量就足以抑制TNBC。这些数据表明，仅由cGAMP-NP组成的最小系统足以调节肿瘤微环境，从而有效地控制PD-L1不敏感的TNBC。
Triple-negative breast cancer (TNBC) has few therapeutic options, and alternative approaches are urgently needed. Stimulator of IFN genes (STING) is becoming an exciting target for therapeutic adjuvants. However, STING resides inside the cell, and the intracellular delivery of CDNs, such as cGAMP, is required for the optimal activation of STING. We show that liposomal nanoparticle-delivered cGAMP (cGAMP-NP) activates STING more effectively than soluble cGAMP. These particles induce innate and adaptive host immune responses to preexisting tumors in both orthotopic and genetically engineered models of basal-like TNBC. cGAMP-NPs also reduce melanoma tumor load, with limited responsivity to anti-PD-L1. Within the tumor microenvironment, cGAMP-NPs direct both mouse and human macrophages (M), reprograming from protumorigenic M2-like phenotype toward M1-like phenotype; enhance MHC and costimulatory molecule expression; reduce M2 biomarkers; increase IFN-gamma-producing T cells; augment tumor apoptosis; and increase CD4(+) and CD8(+) T cell infiltration. Activated T cells are required for tumor suppression, as their depletion reduces antitumor activity. Importantly, cGAMP-NPs prevent the formation of secondary tumors, and a single dose is sufficient to inhibit TNBC. These data suggest that a minimal system comprised of cGAMP-NP alone is sufficient to modulate the tumor microenvironment to effectively control PD-L1-insensitive TNBC.