LILRB4 in tumor-associated macrophage regulates macrophage polarization and glioblastoma progression via STAT3/IL10 axis

IF 2.4 3区生物学 Q2 GENETICS & HEREDITY

Gene Pub Date : 2025-09-30 DOI:10.1016/j.gene.2025.149805

Jie Pei , Chao Li , Qi Liu , Fuchun Miao , Zhou Zheng , Cheng Sun , Bingyan Tao , Jihua Wang , Ling Yang , Peng Liu , Yaping Feng , Cidan Danzhen , Junyi Chen , Yuyang Liu

{"title":"LILRB4 in tumor-associated macrophage regulates macrophage polarization and glioblastoma progression via STAT3/IL10 axis","authors":"Jie Pei , Chao Li , Qi Liu , Fuchun Miao , Zhou Zheng , Cheng Sun , Bingyan Tao , Jihua Wang , Ling Yang , Peng Liu , Yaping Feng , Cidan Danzhen , Junyi Chen , Yuyang Liu","doi":"10.1016/j.gene.2025.149805","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Glioblastoma (GBM), the most aggressive primary brain tumor, exhibits a profoundly immunosuppressive tumor microenvironment (TME) dominated by M2-like tumor-associated macrophages (TAMs). The leukocyte immunoglobulin-like receptor B4 (LILRB4) has emerged as a critical immunoregulatory molecule implicated in cancer progression, yet its role in GBM remains poorly understood. This study investigated the expression, prognostic significance, and functional role of LILRB4 in TAM-mediated immunosuppression and GBM progression.</div></div><div><h3>Methods</h3><div>Expression patterns and prognostic significance of LILRB4 were analyzed using TCGA and validation datasets. Single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), and proteogenomics analyses identified cellular sources and spatial distribution of LILRB4. THP-1 cells were differentiated into TAM-like macrophages using PMA and tumor-conditioned medium (TCM) from GBM cells. LILRB4 was silenced using shRNA, and macrophage polarization markers were assessed by RT-qPCR, western blot, and ELISA.</div></div><div><h3>Results</h3><div>LILRB4 was identified as an independent prognostic factor in glioma, with high expression correlating with poor survival. Multiple bioinformatics approaches revealed strong LILRB4-M2 macrophage associations. ST revealed predominant LILRB4 expression in macrophage clusters with strongest tumor cell co-occurrence, identifying LAIR1 as a potential receptor. Proteogenomics analysis showed strong LILRB4 protein-mRNA correlations and associations with M2 markers. LILRB4 regulated macrophage polarization through the STAT3/IL10 axis. Knockdown reversed M2-like phenotype toward M1-like state, decreasing CD163, IL10, and TGFB1 while increasing IL1B and TNFA. TCM from LILRB4 knockdown macrophages significantly inhibited GBM cell proliferation.</div></div><div><h3>Conclusion</h3><div>LILRB4 might functions as a critical regulator of the immunosuppressive TME in GBM by promoting M2 macrophage polarization through the STAT3/IL10 axis. Targeting LILRB4 represents a promising approach for enhancing immunotherapeutic efficacy in GBM.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"971 ","pages":"Article 149805"},"PeriodicalIF":2.4000,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Gene","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0378111925005943","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}

引用次数: 0

Abstract

Background

Glioblastoma (GBM), the most aggressive primary brain tumor, exhibits a profoundly immunosuppressive tumor microenvironment (TME) dominated by M2-like tumor-associated macrophages (TAMs). The leukocyte immunoglobulin-like receptor B4 (LILRB4) has emerged as a critical immunoregulatory molecule implicated in cancer progression, yet its role in GBM remains poorly understood. This study investigated the expression, prognostic significance, and functional role of LILRB4 in TAM-mediated immunosuppression and GBM progression.

Methods

Expression patterns and prognostic significance of LILRB4 were analyzed using TCGA and validation datasets. Single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), and proteogenomics analyses identified cellular sources and spatial distribution of LILRB4. THP-1 cells were differentiated into TAM-like macrophages using PMA and tumor-conditioned medium (TCM) from GBM cells. LILRB4 was silenced using shRNA, and macrophage polarization markers were assessed by RT-qPCR, western blot, and ELISA.

Results

LILRB4 was identified as an independent prognostic factor in glioma, with high expression correlating with poor survival. Multiple bioinformatics approaches revealed strong LILRB4-M2 macrophage associations. ST revealed predominant LILRB4 expression in macrophage clusters with strongest tumor cell co-occurrence, identifying LAIR1 as a potential receptor. Proteogenomics analysis showed strong LILRB4 protein-mRNA correlations and associations with M2 markers. LILRB4 regulated macrophage polarization through the STAT3/IL10 axis. Knockdown reversed M2-like phenotype toward M1-like state, decreasing CD163, IL10, and TGFB1 while increasing IL1B and TNFA. TCM from LILRB4 knockdown macrophages significantly inhibited GBM cell proliferation.

Conclusion

LILRB4 might functions as a critical regulator of the immunosuppressive TME in GBM by promoting M2 macrophage polarization through the STAT3/IL10 axis. Targeting LILRB4 represents a promising approach for enhancing immunotherapeutic efficacy in GBM.

查看原文本刊更多论文

肿瘤相关巨噬细胞中的LILRB4通过STAT3/IL10轴调控巨噬细胞极化和胶质母细胞瘤进展。

背景：胶质母细胞瘤（GBM）是最具侵袭性的原发性脑肿瘤，具有由m2样肿瘤相关巨噬细胞（tam）主导的深度免疫抑制肿瘤微环境（TME）。白细胞免疫球蛋白样受体B4 （LILRB4）已成为参与癌症进展的关键免疫调节分子，但其在GBM中的作用仍知之甚少。本研究探讨了LILRB4在tam介导的免疫抑制和GBM进展中的表达、预后意义和功能作用。方法：采用TCGA和验证数据分析LILRB4的表达模式及预后意义。单细胞RNA测序（scRNA-seq）、空间转录组学（ST）和蛋白质基因组学分析确定了LILRB4的细胞来源和空间分布。用PMA和TCM将GBM细胞中的THP-1细胞分化为tam样巨噬细胞。采用shRNA沉默LILRB4，采用RT-qPCR、western blot和ELISA检测巨噬细胞极化标记物。结果：LILRB4在胶质瘤中是一个独立的预后因子，其高表达与生存差相关。多种生物信息学方法揭示了LILRB4-M2与巨噬细胞的强烈关联。ST显示，在与最强肿瘤细胞共存的巨噬细胞簇中，主要表达LILRB4，确定LAIR1是潜在的受体。蛋白质基因组学分析显示，LILRB4蛋白mrna与M2标记具有很强的相关性和相关性。LILRB4通过STAT3/IL10轴调控巨噬细胞极化。敲低将m2样表型逆转为m1样状态，降低CD163、IL10和TGFB1，同时增加IL1B和TNFA。中药敲除LILRB4可显著抑制巨噬细胞的增殖。结论：LILRB4可能通过STAT3/IL10轴促进M2巨噬细胞极化，从而在GBM中发挥免疫抑制TME的关键调节作用。靶向LILRB4是提高GBM免疫治疗效果的一种有希望的方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Gene 生物-遗传学

CiteScore

6.10

自引率

2.90%

发文量

718

审稿时长

42 days

期刊介绍： Gene publishes papers that focus on the regulation, expression, function and evolution of genes in all biological contexts, including all prokaryotic and eukaryotic organisms, as well as viruses.