Dual-mechanism based CTLs infiltration enhancement initiated by Nano-sapper potentiates immunotherapy against immune-excluded tumors
Dual-mechanism based CTLs infiltration enhancement initiated by Nano-sapper potentiates immunotherapy against immune-excluded tumors
复制标题
Nano-sapper 启动的基于双机制的 CTL 浸润增强增强了针对免疫排斥肿瘤的免疫治疗
DOI：
10.1038/s41467-020-14425-7
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发表时间：
2020-01-30
影响因子：
16.6
通讯作者：
Chen, Jun
中科院分区：
文献类型：
--
作者：
Huang, Yukun;Chen, Yu;Chen, Jun
免疫排斥肿瘤（IET）免疫治疗的失败主要归因于肿瘤内细胞毒性T细胞（CTL）的缺乏。主要障碍是过多的基质、缺陷的血管和募集CTL的信号缺乏。在这里，我们报告了一种基于双重机制的CTL浸润增强剂，Nano-sapper，它可以同时减少肿瘤微环境中的物理障碍，并招募CTL来增强IET中的免疫治疗。Nano-sapper由共装载抗纤维化磷酸盐修饰的α-mangostin和编码免疫增强细胞因子LIGHT的质粒的核心组成。Nano-sapper通过逆转异常活化的成纤维细胞、减少胶原沉积、使肿瘤内血管正常化以及原位刺激淋巴细胞募集化学引诱物的表达，为CTL浸润铺平道路，诱导肿瘤内三级淋巴结构，从而重塑肿瘤微环境并增强针对IET的检查点抑制剂。这项研究表明，抗纤维化药物和免疫增强细胞因子的组合可能代表了一种促进免疫治疗IET的方式。
The failure of immunotherapies in immune-excluded tumor (IET) is largely ascribed to the void of intratumoral cytotoxic T cells (CTLs). The major obstacles are the excessive stroma, defective vasculatures and the deficiency of signals recruiting CTLs. Here we report a dual-mechanism based CTLs infiltration enhancer, Nano-sapper, which can simultaneously reduce the physical obstacles in tumor microenvironment and recruiting CTLs to potentiate immunotherapy in IET. Nano-sapper consists a core that co-loaded with antifibrotic phosphates-modified α-mangostin and plasmid encoding immune-enhanced cytokine LIGHT. Through reversing the abnormal activated fibroblasts, decreasing collagen deposition, normalizing the intratumoral vasculatures, and in situ stimulating the lymphocyte-recruiting chemoattractants expression, Nano-sapper paves the road for the CTLs infiltration, induces the intratumoral tertiary lymphoid structures, thus reshapes tumor microenvironment and potentiates checkpoint inhibitor against IET. This study demonstrates that the combination of antifibrotic agent and immune-enhanced cytokine might represent a modality in promoting immunotherapy against IET.