scRNA-seq和蛋白質(zhì)組學(xué)揭示了m2樣巨噬細(xì)胞在惡性膠質(zhì)瘤中關(guān)鍵作用

2023年5月，福建醫(yī)科大學(xué)附屬醫(yī)院神經(jīng)外科;福建醫(yī)科大學(xué)附屬醫(yī)院福建省婦兒醫(yī)院婦科;莆田學(xué)院附屬醫(yī)院神經(jīng)外科;福州平潭綜合實(shí)驗(yàn)區(qū)醫(yī)院 (Department of Neurosurgery, Fujian Medical University Union Hospital,Fuzhou, China；Fujian Medical University, Fuzhou, China；Department of Gynaecology, Fujian Provincial Maternity and Children's Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, China；Department of Neurosurgery, Affiliated Hospital of Putian University, Putian,China；Pingtan Comprehensive Experimental Area Hospital, Fuzhou, China) Guiting You老師研究團(tuán)隊(duì)在《CNS Neuroscience & Therapeutics》上發(fā)表論文：

“scRNA-seq and proteomics reveal the distinction of M2-like macrophages between primary and recurrent malignant glioma and its critical role in the recurrence”

“scRNA-seq和蛋白質(zhì)組學(xué)揭示了m2樣巨噬細(xì)胞在原發(fā)性和復(fù)發(fā)性惡性膠質(zhì)瘤中的差異及其在復(fù)發(fā)中的關(guān)鍵作用”

Abstract：

Aims: Tumor-associated macrophages (TAMs) in the immune microenvironment play an important role in the increased drug resistance and recurrence of malignant glioma, but the mechanism remains incompletely inventoried. The focus of this study was to investigate the distinctions of M2-like TAMs in the immune microenvironment between primary and recurrent malignant glioma and its influence in the recurrence.

Methods: We employed single-cell RNA sequencing to construct a single-cell atlas for a total of 23,010 individual cells from 6 patients with primary or recurrent malignant glioma and identified 5 cell types, including TAMs and malignant cells. Immunohistochemical techniques and proteomics analysis were performed to investigate the role of intercellular interaction between malignant cells and TAMs in the recurrence of malignant glioma.

Results: Six subgroups of TAMs were annotated and M2-like TAMs were found to increase in recurrent malignant glioma significantly. A pseudotime trajectory and a dynamic gene expression profiling during the recurrence of malignant glioma were reconstructed. Up-regulation of several cancer pathways and intercellular interaction-related genes are associated with the recurrence of malignant glioma. Moreover, the M2-like TAMs can activate the PI3K/Akt/HIF-1α/CA9 pathway in the malignant glioma cells via SPP1-CD44-mediated intercellular interaction. Interestingly, high expression of CA9 can trigger the immunosuppressive response in the malignant glioma, thus promoting the degree of malignancy and drug resistance.

Conclusion: Our study uncovers the distinction of M2-like TAMs between primary and recurrent glioma, which offers unparalleled insights into the immune microenvironment of primary and recurrent malignant glioma.

摘要：

目的:免疫微環(huán)境中的腫瘤相關(guān)巨噬細(xì)胞(Tumor-associated macrophages, tam)在惡性膠質(zhì)瘤耐藥增加和復(fù)發(fā)中發(fā)揮重要作用，但其機(jī)制尚不清楚。本研究的重點(diǎn)是探討原發(fā)性和復(fù)發(fā)性惡性膠質(zhì)瘤免疫微環(huán)境中m2樣tam的差異及其對(duì)復(fù)發(fā)的影響。

方法:采用單細(xì)胞RNA測(cè)序技術(shù)，構(gòu)建來自6例原發(fā)性或復(fù)發(fā)性惡性膠質(zhì)瘤患者的23,010個(gè)細(xì)胞的單細(xì)胞圖譜，鑒定出包括tam細(xì)胞和惡性細(xì)胞在內(nèi)的5種細(xì)胞類型。通過免疫組織化學(xué)技術(shù)和蛋白質(zhì)組學(xué)分析，研究惡性細(xì)胞與tam之間的細(xì)胞間相互作用在惡性膠質(zhì)瘤復(fù)發(fā)中的作用。

結(jié)果:6個(gè)tam亞組被注釋，發(fā)現(xiàn)復(fù)發(fā)性惡性膠質(zhì)瘤中m2樣tam顯著增加。重建惡性膠質(zhì)瘤復(fù)發(fā)期間的假時(shí)間軌跡和動(dòng)態(tài)基因表達(dá)譜。幾種腫瘤通路和細(xì)胞間相互作用相關(guān)基因的上調(diào)與惡性膠質(zhì)瘤的復(fù)發(fā)有關(guān)。此外，m2樣tam可以通過spp1 - cd44介導(dǎo)的細(xì)胞間相互作用激活惡性膠質(zhì)瘤細(xì)胞中的PI3K/Akt/HIF-1α/CA9通路。有趣的是，在惡性膠質(zhì)瘤中，CA9的高表達(dá)可引發(fā)免疫抑制反應(yīng)，從而促進(jìn)惡性程度和耐藥。

結(jié)論:研究人員的研究揭示了原發(fā)性和復(fù)發(fā)性膠質(zhì)瘤之間m2樣tam的差異，為原發(fā)性和復(fù)發(fā)性惡性膠質(zhì)瘤的免疫微環(huán)境提供了見解。

該論文中，人膠質(zhì)瘤U87細(xì)胞及其慢病毒轉(zhuǎn)染細(xì)胞的體外培養(yǎng)是使用Ausbian特級(jí)胎牛血清完成的。