Zheng Wanting, Yu Wangjianfei, Hua Ruheng, He Jun, Wu Nuwa, Tian Siyun, Huang Wentao, Qin Lei
Department of General Surgery, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, China.
Suzhou Medical College of Soochow University, Soochow University, Suzhou, China.
Transl Cancer Res. 2024 Jul 31;13(7):3200-3216. doi: 10.21037/tcr-24-201. Epub 2024 Jul 24.
Triggering receptor expressed on myeloid cells 2 (TREM2), a transmembrane immunoglobulin-superfamily receptor, is expressed primarily on cells such as macrophages and dendritic cells. TREM2 has been shown to be associated with diseases such as neurodegeneration, fatty liver, obesity, and atherosclerosis. Currently, it has become one of the hotspots in oncology research. However, the role of TREM2 in pan-cancer, especially pancreatic cancer, remains unclear.
We used the Tumor-immune System Interactions Database (TISIDB) to explore TREM2 expression differences, Tumor Immune Single-cell Hub 2 (TISCH2) to explore TREM2 expression distribution, Tumor IMmune Estimation Resource 2.0 (TIMER 2.0) to explore immune infiltration, cBio Cancer Genomics Portal (cBioPortal) to explore genetic variation, Genomics of Drug Sensitivity in Cancer (GDSC) to explore drug resistance, and Kaplan-Meier plotter database to explore the relationship between TREM2 and prognosis in pancreatic cancer. In addition, we used The Cancer Genome Atlas-pancreatic adenocarcinoma (TCGA-PAAD) and normal pancreas samples from the Genotype-Tissue Expression (GTEx) databases to explore the relationship between TREM2 and lymph node metastasis. We verified the protein level of TREM2 in pancreatic cancer by Human Protein Atlas (HPA) and western blotting and detected the colocalization of TREM2 with malignant cell markers by multiplex immunohistochemistry (mIHC). Finally, we identified the tumor-promoting role of TREM2 in pancreatic cancer via experiments, such as cell cycle assays, colony formation assays, and transwell migration and invasion assays.
Our results showed that TREM2 was differentially expressed in various tumors according to different molecular and immune subtypes of pan-cancer. It was found that TREM2 was mainly expressed in monocytes/macrophages. In addition, our study showed that TREM2 expression was closely associated with macrophages in the tumor microenvironment (TME) of pan-cancer. TREM2 was shown to be related to anti-inflammatory and immunosuppressive effects in most cancers. Furthermore, we found that amplification was the main somatic mutation of TREM2 in pan-cancer. Further correlational analysis revealed a significant negative association of TREM2 expression with sensitivity to AZD8186, which is a selective inhibitor of PI3K, but not gemcitabine and paclitaxel. Finally, through the knockdown and overexpression of TREM2, our findings verified that TREM2 on cancer cells promoted the progression of PAAD.
In conclusion, our comprehensive analysis identified that TREM2 expression level was correlated with the TME and the immunosuppressive effects. In particular, our study indicated that TREM2 was involved in the progression of pancreatic cancer.
髓系细胞触发受体2（TREM2）是一种跨膜免疫球蛋白超家族受体，主要在巨噬细胞和树突状细胞等细胞上表达。TREM2已被证明与神经退行性疾病、脂肪肝、肥胖症和动脉粥样硬化等疾病有关。目前，它已成为肿瘤学研究的热点之一。然而，TREM2在泛癌，尤其是胰腺癌中的作用仍不清楚。
我们使用肿瘤-免疫系统相互作用数据库（TISIDB）探索TREM2表达差异，肿瘤免疫单细胞中心2（TISCH2）探索TREM2表达分布，肿瘤免疫估计资源2.0（TIMER 2.0）探索免疫浸润，cBio癌症基因组学门户（cBioPortal）探索基因变异，癌症药物敏感性基因组学（GDSC）探索耐药性，以及Kaplan-Meier绘图仪数据库探索TREM2与胰腺癌预后的关系。此外，我们使用癌症基因组图谱-胰腺腺癌（TCGA-PAAD）和基因型-组织表达（GTEx）数据库中的正常胰腺样本探索TREM2与淋巴结转移的关系。我们通过人类蛋白质图谱（HPA）和蛋白质免疫印迹法验证了胰腺癌中TREM2的蛋白水平，并通过多重免疫组织化学（mIHC）检测了TREM2与恶性细胞标志物的共定位。最后，我们通过细胞周期分析、集落形成分析以及Transwell迁移和侵袭分析等实验确定了TREM2在胰腺癌中的促肿瘤作用。
我们的结果表明，根据泛癌的不同分子和免疫亚型，TREM2在各种肿瘤中差异表达。发现TREM2主要在单核细胞/巨噬细胞中表达。此外，我们的研究表明，TREM2表达与泛癌肿瘤微环境（TME）中的巨噬细胞密切相关。在大多数癌症中，TREM2显示出与抗炎和免疫抑制作用有关。此外，我们发现扩增是泛癌中TREM2的主要体细胞突变。进一步的相关性分析显示，TREM2表达与PI3K选择性抑制剂AZD8186的敏感性呈显著负相关，但与吉西他滨和紫杉醇无关。最后，通过TREM2的敲低和过表达，我们的研究结果证实癌细胞上的TREM2促进了PAAD的进展。
总之，我们的综合分析确定TREM2表达水平与TME和免疫抑制作用相关。特别是，我们的研究表明TREM2参与了胰腺癌的进展。
