TREM2 mediates MHCII-associated CD4+ T cell response against gliomas.
TREM2 mediates MHCII-associated CD4+ T cell response against gliomas.
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TREM2 介导 MHCII 相关 CD4 T 细胞针对神经胶质瘤的反应。
DOI：
10.1093/neuonc/noad214
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发表时间：
2023
期刊：
影响因子：
15.9
通讯作者：
Quiñones-H
中科院分区：
文献类型：
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作者：
Zheng,Jiaying;Wang,Lingxiao;Zhao,Shunyi;Zhang,Wenjing;Chang,Yuzhou;Bosco,DaleB;Huang,Tao;Dheer,Aastha;Gao,Shan;Xu,Shengze;Ayasoufi,Katayoun;Al-Kharboosh,Rawan;Qi,Fangfang;Xie,Manling;Johnson,AaronJ;Dong,Haidong;Quiñones-H
背景髓系细胞占胶质母细胞瘤（GBM）肿瘤总重量的50%，并参与促进肿瘤进展和免疫抑制。调节骨髓细胞对肿瘤的反应已成为癌症治疗的一种有前途的新方法。在这方面，我们专注于触发受体表达的髓样细胞2（TREM 2），这是最近出现的一种新的免疫调节剂在外周tumors.MethodsWe研究了TREM 2的表达谱在各种患者的肿瘤样品和GBM患者和GL 261小鼠胶质瘤模型进行单细胞转录组学分析。我们利用多种小鼠胶质瘤模型，并采用最先进的技术，如体内2-光子成像，光谱流式细胞术，和体外培养试验，研究TREM 2在髓样细胞介导的肿瘤细胞吞噬，抗原呈递，和CD 4+应答结果我们的研究显示，与其他类型的肿瘤相比，脑肿瘤中的TREM 2表达水平显着升高，患者TREM 2主要定位于肿瘤相关的髓样细胞中，并且在几乎所有的小胶质细胞以及各种亚型的巨噬细胞中高度表达。令人惊讶的是，在临床前胶质瘤模型中，TREM 2缺陷并没有带来有益的效果;相反，它加速了胶质瘤的进展。通过详细的研究，我们确定了TREM 2缺陷损害了肿瘤骨髓细胞吞噬肿瘤细胞的能力，并导致MHCII表达减少。这种缺陷进一步显着降低了肿瘤hemispheres.ConclusionsOur研究揭示了以前未被认识到的肿瘤髓样TREM 2的保护作用内的CD 4 +T细胞的存在。具体地说，我们发现TREM 2增强了肿瘤细胞的吞噬作用，并通过促进MHCII相关的CD 4 + T细胞对胶质瘤的应答来促进免疫应答。
BackgroundMyeloid cells comprise up to 50% of the total tumor mass in glioblastoma (GBM) and have been implicated in promoting tumor progression and immunosuppression. Modulating the response of myeloid cells to the tumor has emerged as a promising new approach for cancer treatment. In this regard, we focus on the Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), which has recently emerged as a novel immune modulator in peripheral tumors.MethodsWe studied the TREM2 expression profile in various patient tumor samples and conducted single-cell transcriptomic analysis in both GBM patients and the GL261 mouse glioma model. We utilized multiple mouse glioma models and employed state-of-the-art techniques such asinvivo2-photon imaging, spectrum flow cytometry, andin vitroco-culture assays to study TREM2 function in myeloid cell-mediated phagocytosis of tumor cells, antigen presentation, and response of CD4+T cells within the tumor hemispheres.ResultsOur research revealed significantly elevated levels of TREM2 expression in brain tumors compared to other types of tumors in patients. TREM2 was predominantly localized in tumor-associated myeloid cells and was highly expressed in nearly all microglia, as well as various subtypes of macrophages. Surprisingly, in preclinical glioma models, TREM2 deficiency did not confer a beneficial effect; instead, it accelerated glioma progression. Through detailed investigations, we determined that TREM2 deficiency impaired the ability of tumor-myeloid cells to phagocytose tumor cells and led to reduced expression of MHCII. This deficiency further significantly decreased the presence of CD4+T cells within the tumor hemispheres.ConclusionsOur study unveiled a previously unrecognized protective role of tumor-myeloid TREM2. Specifically, we found that TREM2 enhances the phagocytosis of tumor cells and promotes an immune response by facilitating MHCII-associated CD4+T-cell responses against gliomas.