EMP3 mediates glioblastoma-associated macrophage infiltration to drive T cell exclusion.
EMP3 mediates glioblastoma-associated macrophage infiltration to drive T cell exclusion.
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EMP3 介导胶质母细胞瘤相关巨噬细胞浸润以驱动 T 细胞排斥
DOI：
10.1186/s13046-021-01954-2
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发表时间：
2021-05-08
期刊：
影响因子：
--
通讯作者：
Zhan R
中科院分区：
文献类型：
--
作者：
Chen Q;Jin J;Huang X;Wu F;Huang H;Zhan R
背景免疫抑制性肿瘤微环境是胶质母细胞瘤（GBM）发生和发展的关键因素，其特征是肿瘤相关巨噬细胞（tumour-associated macrophages，TAMs）丰富而浸润性T细胞缺乏。在这项研究中，我们研究是否上皮膜蛋白3（EMP 3）在GBM的免疫调节中起着至关重要的作用。MethodsTCGA和CGGA野生型IDH 1 GBM的转录谱用于生物信息学分析。通过体内和体外实验验证了EMP 3在GBM中的作用。结果EMP 3与GBM中的免疫抑制有关。GBM区域中EMP 3的升高伴随着PD-L1的高表达和丰富的M2 TAM募集，但存在T细胞浸润湖。我们发现EMP 3是M2 TAM极化和募集中的有效蛋白，其损害GBM细胞分泌CCL 2和TGF-β1的能力。EMP 3通过抑制巨噬细胞分泌CXCL 9和CXCL 10抑制T细胞浸润GBM肿瘤，并导致抗PD 1治疗的有效应答。结论EMP 3是一种重要的免疫抑制因子，可募集GBM中的TAM，抑制肿瘤内T细胞浸润，促进肿瘤进展，是一个潜在的治疗靶点。
BackgroundThe immunosuppressive tumour microenvironment is a critical factor in the initiation and progression of glioblastoma (GBM), which is characterized by an abundance of tumour-associated macrophages (TAMs) but a paucity of infiltrating T cells. In this research, we studied whether epithelial membrane protein 3 (EMP3) plays a crucial role in immune modulation in GBM.MethodsTCGA and CGGA transcriptomic profiles of wild-type IDH1 GBM were used for bioinformatic analysis. The role of EMP3 in GBM was validated throughin vivoandin vitroexperiments. Human GBM specimens were collected and evaluated using immunofluorescence analysis.ResultsEMP3 was associated with immunosuppression in GBM. Elevated EMP3 in GBM areas was accompanied by high expression of PD-L1 and abundant M2 TAM recruitment but a lake of T cell infiltration. We found that EMP3 was a potent protein in M2 TAM polarization and recruitment that impaired the ability of GBM cells to secrete CCL2 and TGF-β1. Furthermore, EMP3 suppressed T cell infiltration into GBM tumours by inhibiting the secretion of CXCL9 and CXCL10 by macrophages and led to an effective response to anti-PD1 therapy.ConclusionsEMP3 is thus a critical immunosuppressive factor for recruiting TAMs in GBM and suppressing intratumoural T cell infiltration to facilitate tumour progression and is a potential therapeutic target.
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