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首页> 外文期刊>Biomaterials Science >The lipid platform increases the activity of STING agonists to synergize checkpoint blockade therapy against melanoma
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The lipid platform increases the activity of STING agonists to synergize checkpoint blockade therapy against melanoma

机译：脂质平台增加了刺痛剂的活性来协同检查点阻断治疗对黑色素瘤

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摘要

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.
机译：对于免疫抑制肿瘤微环境，黑色素瘤的PD-1 / PD-L1免疫检查点抑制（ICI）治疗的反应率保持低位。迫切需要新的策略协同ici治疗。最近出现了干扰素基因刺激剂（刺痛）的刺激剂作为克服免疫抑制的关键途径。这里，2'3'循环鸟苷一磷酸二磷酸腺苷（CGAMP），通用刺痛剂，包封成与甘露糖（LP-CGAMP）缀合的树突细胞（DC） - 特异性细胞溶质递送的脂质纳米粒子。 LP-CGAMP诱导的刺痛相关的促炎和腹腔内注射LP-CGAMP增加了DC成熟和CD8（+）T细胞渗透，与游离CGAMP更有效地更有效地获得。考虑到响应于刺痛激活的PD-L1对肿瘤细胞的上调，我们进一步测试了LP-CGAMP和抗PD-L1的组合治疗，并观察到B16F10和BRAF-突变的鼠黑色素瘤模型中的优异抗肿瘤效果。我们的研究结果证明了CGAMP的靶向递送可以在黑色素瘤中促进PD-L1阻断治疗，并且组合免疫治疗具有产生持久的抗肿瘤作用的巨大潜力。

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  • 来源
    《Biomaterials Science》 |2021年第3期|共9页
  • 作者

    Li Kesang; Ye Yingyi; Liu Liqin; Sha Qian; Wang Xiaolu; Jiao Ting; Zhang Li; Wang Jinyan;

  • 作者单位

    Univ Chinese Acad Sci Dept Hematol &

    Oncol Hwa Mei Hosp Ningbo 315000 Zhejiang Peoples R China;

    Univ Chinese Acad Sci Hwa Mei Hosp Dept Dermatol Ningbo 315010 Zhejiang Peoples R China;

    Univ Chinese Acad Sci Hwa Mei Hosp Dept Dermatol Ningbo 315010 Zhejiang Peoples R China;

    Matern &

    Child Hlth Hosp Dept Dermatol Yuyao 315400 Zhejiang Peoples R China;

    Univ Chinese Acad Sci Hwa Mei Hosp Dept Dermatol Ningbo 315010 Zhejiang Peoples R China;

    Univ Chinese Acad Sci Hwa Mei Hosp Dept Dermatol Ningbo 315010 Zhejiang Peoples R China;

    Univ Chinese Acad Sci Hwa Mei Hosp Dept Dermatol Ningbo 315010 Zhejiang Peoples R China;

    Univ Chinese Acad Sci Hwa Mei Hosp Dept Dermatol Ningbo 315010 Zhejiang Peoples R China;

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  • 正文语种 eng
  • 中图分类 分子生物学;
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