Mechanism of LINC01018/miR-182-5p/Rab27B in the immune escape through PD-L1-mediated CD8+ T cell suppression in glioma
Su Hu, Guoshuo Chen, Aiping Luo, Hailin Zhao, Dan Li, Biao Peng, Jike Du, Dongdong Luo
Abstract
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. 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. 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. 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.