LINC01018/miR-182-5p/Rab27B在胶质瘤中通过PD-L1介导的CD8 T细胞抑制实现免疫逃逸的机制

Mechanism of LINC01018/miR-182-5p/Rab27B in the immune escape through PD-L1-mediated CD8 T cell suppression in glioma.

作者信息

Hu Su, Chen Guoshuo, Luo Aiping, Zhao Hailin, Li Dan, Peng Biao, Du Jike, Luo Dongdong

机构信息

Department of Neurosurgery, Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China.

Department of Intervention, the Affiliated Cancer Hospital, Guangzhou Institute of Cancer Research, Guangzhou Medical University, Guangzhou, 510095, China.

出版信息

Biol Direct. 2025 May 21;20(1):61. doi: 10.1186/s13062-025-00651-w.

DOI:10.1186/s13062-025-00651-w

PMID:40399992

Abstract

BACKGROUND

Glioma is a malignant tumor associated with poorer prognosis. This study aims to elucidate the mechanism of LINC01018/miR-182-5p/Rab27B axis in PD-L1-mediated CD8 T cell suppression in the progression of gliomas.

METHODS

LINC01018, miR-182-5p, and Rab27B expression levels in glioblastoma tissues were measured. The proportion of infiltrating macrophages and monocytes and CD8 T cell function were assessed. The relationship between miR-182-5p and Rab27B was analyzed. Glioma cell activity, invasion, and migration were measured. The expression of E-cadherin, N-cadherin, Vimentin, PD-L1, iNOS, and CD206 was determined. Glioma cell-derived EVs were isolated, and the co-localization of Rab27B and PD-L1 and the binding of Rab27B to PD-L1 were analyzed. The endocytosis of EVs by microglia was assayed. The impact of LINC01018/miR-182-5p/Rab27B on glioma growth was observed. The function of macrophages and CD8 T cells in tumors was analyzed.

RESULTS

Rab27B was downregulated, and infiltrating macrophages and monocytes were increased in glioblastoma. miR-182-5p inhibited Rab27B expression. Rab27B knockdown reverses the inhibitory effect of LINC01018 overexpression on glioma cell growth. Glioma cells-derived EVs with low Rab27B expression carried more PD-L1 to increase PD-L1 expression and M2 polarization in microglia. LINC01018 overexpression reduced macrophages in orthotopic tumors. CD8 T cell numbers showed no significant difference, but TIM-3 increased and IFN-γ decreased. miR-182-5p inhibition enhanced the therapeutic effect of anti-PD-L1, which was reversed after glioma cell-derived EVs.

CONCLUSION

LINC01018 promotes PD-L1-mediated CD8 T cell suppression via the miR-182-5p/Rab27B axis in glioma cell-derived EVs, thereby contributing to immune escape in gliomas.

摘要

背景

胶质瘤是一种预后较差的恶性肿瘤。本研究旨在阐明长链非编码RNA LINC01018/微小RNA-182-5p/Rab27B轴在胶质瘤进展过程中PD-L1介导的CD8 T细胞抑制作用中的机制。

方法

检测胶质母细胞瘤组织中LINC01018、微小RNA-182-5p和Rab27B的表达水平。评估浸润性巨噬细胞和单核细胞的比例以及CD8 T细胞功能。分析微小RNA-182-5p与Rab27B之间的关系。检测胶质瘤细胞的活性、侵袭和迁移能力。测定E-钙黏蛋白、N-钙黏蛋白、波形蛋白、PD-L1、诱导型一氧化氮合酶和CD206的表达。分离胶质瘤细胞衍生的细胞外囊泡，分析Rab27B与PD-L1的共定位以及Rab27B与PD-L1的结合情况。检测小胶质细胞对细胞外囊泡的内吞作用。观察LINC01018/微小RNA-182-5p/Rab27B对胶质瘤生长的影响。分析肿瘤中巨噬细胞和CD8 T细胞的功能。

结果

在胶质母细胞瘤中，Rab27B表达下调，浸润性巨噬细胞和单核细胞增加。微小RNA-182-5p抑制Rab27B的表达。敲低Rab27B可逆转LINC01018过表达对胶质瘤细胞生长的抑制作用。Rab27B表达低的胶质瘤细胞衍生的细胞外囊泡携带更多的PD-L1，从而增加小胶质细胞中PD-L1的表达和M2极化。LINC01018过表达减少原位肿瘤中的巨噬细胞。CD8 T细胞数量无显著差异，但T细胞免疫球蛋白和粘蛋白结构域3（TIM-3）增加，γ干扰素（IFN-γ）减少。抑制微小RNA-182-5p可增强抗PD-L1的治疗效果，而胶质瘤细胞衍生的细胞外囊泡作用后这种增强作用被逆转。