Zhao Yang, Zhang Cangang, Zhu Yanan, Ding Xi, Zhou Yikun, Lv Hongjun, Lin Yuxuan, Wu Yuan, Shi Bingyin, Fu Jiao
Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Endocr Relat Cancer. 2022 Jan 10;29(2):71-86. doi: 10.1530/ERC-21-0297.
The immunosuppressive microenvironment is associated with poor prognosis in papillary thyroid cancer (PTC); however, the molecular mechanisms involved are unknown. Among the triggering receptors expressed on myeloid cell (TREM) family, we found that TREM1 expression in PTC was significantly higher than that in normal tissues. TREM1 overexpression was associated with BRAFV600E profiles and advanced tumor stages. Furthermore, TREM1 mRNA expression was negatively correlated with promoter methylation status. Specifically, hypomethylation of CpG site cg06196379 in the TREM1 promoter was related with poor patient disease-free survival (DFS) and a high PTC recurrence rate. Mechanistically, TREM1 was mainly expressed in malignant epithelial cells but not in macrophages in PTC by single-cell analysis. PTC tissues with high TREM1 levels had enhanced infiltration of regulatory T cells (Tregs) and decreased infiltration of CD8+ T cells. Our study confirms that hypomethylation-mediated overexpression of TREM1 in PTC cells promotes an immunosuppressive microenvironment by enhancing Treg infiltration. We recommend the future use of therapeutic strategy targeting TREM1 for the treatment of PTC.
免疫抑制微环境与甲状腺乳头状癌（PTC）的不良预后相关；然而，其中涉及的分子机制尚不清楚。在髓样细胞表达的触发受体（TREM）家族中，我们发现PTC中TREM1的表达显著高于正常组织。TREM1过表达与BRAFV600E特征及肿瘤晚期相关。此外，TREM1 mRNA表达与启动子甲基化状态呈负相关。具体而言，TREM1启动子中CpG位点cg06196379的低甲基化与患者无病生存期（DFS）差和PTC复发率高有关。从机制上讲，通过单细胞分析发现TREM1主要表达于PTC的恶性上皮细胞而非巨噬细胞中。TREM1水平高的PTC组织中调节性T细胞（Tregs）浸润增强，而CD8 + T细胞浸润减少。我们的研究证实，PTC细胞中TREM1的低甲基化介导的过表达通过增强Treg浸润促进免疫抑制微环境。我们建议未来使用靶向TREM1的治疗策略来治疗PTC。
