外泌体microRNA调控肿瘤微环境内Tregs分化与功能促进EGFR突变型NSCLC免疫逃逸的机制

NSCLC patients with EGFR mutations have poor response to immunotherapy. However, the mechanisms have not yet been addressed. Our preclinical and clinical studies showed that lower expression of PD-L1 was associated with more Tregs infiltration. This finding prompted Tregs as major effectors of immune escape in EGFR-driven NSCLC. Our pre-experiment found: 1.Tregs could take up tumor-derived exosomes (TEXs). 2.The expression of miR-155-5p was higher in EGFR-mutated TEX than in wild-type. 3. Bioinformatic analysis found that miR-155-5p targeted histone deacetylase 9 (HDAC9) and HDAC9 was negatively controlled by miR-155-5p. It is reported that HDAC9-FoxP3 complex regulated the differentiation and function of Tregs. Taken together, we speculate that EGFR-mutated NSCLC cells negatively control the expression of HDAC9 by secretion of TEX with enriched miR-155-5p. Decreased HDAC9 affects the function of HDAC9-FoxP3 complex, and eventually, enhances the Treg-mediated suppression. In this current project, we will use multiple techniques and models in vitro and vivo to comprehensively investigate the role of TEX-miR-155-5p in regulating of Tregs. Ultimately, we determine to provide innovative theory basis for immunotherapy in the treatment of patients with EGFR mutations.

EGFR突变型NSCLC对PD-1/PD-L1抑制剂效果差，但机制未明。EGFR突变型NSCLC肿瘤微环境中Tregs浸润明显增加，提示Tregs可能在免疫逃逸中发挥关键作用。课题组前期研究发现：Tregs可摄取肿瘤细胞分泌的外泌体，EGFR突变型NSCLC分泌的外泌体富含miR-155-5p，生信分析发现其潜在靶点是HDAC9；而miR-155-5p可下调HDAC9的表达。结合既往研究，我们推测EGFR突变型NSCLC通过分泌富含miR-155-5p的外泌体负向调控HDAC9，继而影响HDAC9-FoxP3复合体功能，最终促进Tregs发挥免疫逃逸功能。因此，本课题拟通过细胞共培养、动物模型、临床样本验证等探讨外泌体miR-155-5p调控Tregs分化和功能的分子机制，为EGFR突变型NSCLC的免疫治疗提供新的理论依据。

EGFR突变型NSCLC对PD-1/PD-L1抑制剂效果差，但机制未明。本项目前期通过收集病人标本并进行多色流式细胞术等分析发现，EGFR突变型NSCLC肿瘤微环境中Tregs浸润明显增加。在研期间，我们发现EGFR突变型肿瘤并非直接调控Treg极化，而是存在通过微环境互作的间接调控；EGFR突变型肿瘤通过分泌外泌体直接促进M2型巨噬细胞的极化，进而诱导Treg细胞的极化；单细胞及Bulk RNA等多组学测序验证了以上机制。本项目的完成将部分阐明EGFR突变型NSCLC患者对PD-1/PD-L1抑制剂效果差的分子机制，探索外泌体调控Tregs分化和功能的分子机制，从而为理解肺癌免疫微环境调控提供一个新视角，为EGFR突变型NSCLC的免疫治疗提供新的理论支持和治疗思路。

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