Li Kesang, Ye Yingyi, Liu Liqin, Sha Qian, Wang Xiaolu, Jiao Ting, Zhang Li, Wang Jinyan
Department of Hematology and Oncology, Hwa Mei Hospital, University of Chinese Academy of Sciences, Zhejiang Province, Ningbo 315000, China.
Biomater Sci. 2021 Feb 7;9(3):765-773. doi: 10.1039/d0bm00870b. Epub 2020 Nov 17.
The response rate to PD-1/PD-L1 immune checkpoint inhibition (ICI) therapy in melanoma remains low due to the immunosuppressive tumor microenvironment. Novel strategies synergizing ICI treatment are urgently sought after. Activation of the stimulator of interferon genes (STING) has recently emerged as a critical pathway to overcome immunosuppression. Herein, 2'3' cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), a universal STING agonist, was encapsulated into lipid nanoparticles conjugated with mannose (LP-cGAMP) for dendritic cell (DC)-specific cytosolic delivery. LP-cGAMP induced STING-related pro-inflammatory and intratumoral injections of LP-cGAMP increased DC maturation and CD8 T cell infiltration more efficiently compared to free cGAMP. Given the upregulation of PD-L1 on tumor cells in response to STING activation, we further tested the combination therapy of LP-cGAMP and anti-PD-L1 and observed a superior antitumor effect in B16F10 and BRAF-mutated murine melanoma models. Our findings prove that targeted delivery of cGAMP can synergize PD-L1 blockade therapy in melanoma and the combinational immune therapy has a great potential to produce a long-lasting anti-tumor effect.
由于免疫抑制性肿瘤微环境，黑色素瘤对PD-1/PD-L1免疫检查点抑制（ICI）疗法的反应率仍然很低。迫切需要新的策略来协同ICI治疗。干扰素基因刺激物（STING）的激活最近已成为克服免疫抑制的关键途径。在此，2'3'环磷酸鸟苷-磷酸腺苷（cGAMP），一种通用的STING激动剂，被封装到与甘露糖偶联的脂质纳米颗粒（LP-cGAMP）中，用于树突状细胞（DC）特异性胞质递送。与游离cGAMP相比，LP-cGAMP诱导的与STING相关的促炎反应和瘤内注射LP-cGAMP能更有效地促进DC成熟和CD8 T细胞浸润。鉴于肿瘤细胞上PD-L1的上调是对STING激活的反应，我们进一步测试了LP-cGAMP和抗PD-L1的联合疗法，并在B16F10和BRAF突变的小鼠黑色素瘤模型中观察到了卓越的抗肿瘤效果。我们的研究结果证明，cGAMP的靶向递送可以协同黑色素瘤中的PD-L1阻断疗法，并且联合免疫疗法具有产生持久抗肿瘤效果的巨大潜力。
