Center for Infection and Immunity, Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China.
Department of Clinical Laboratory, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China.
J Exp Clin Cancer Res. 2024 Aug 13;43(1):224. doi: 10.1186/s13046-024-03124-6.
High infiltration of tumor-associated macrophages (TAMs) is associated with tumor promotion and immunosuppression. The triggering receptor expressed on myeloid cells 2 (TREM2) is emerged as a key immunosuppressive regulator for TAMs, however, how TREM2-expressing TAMs are recruited and what ligands TREM2 interacts with to mediate immunosuppression is unknown.
Flow cytometry and single-cell RNA sequencing were used to analyze TREM2 expression. Mechanistically, mass spectrometry and immunoprecipitation were employed to identify proteins binding to TREM2. Phagocytosis and co-culture experiments were used to explore the in vitro functions of galectin3-TREM2 pair. Establishment of TREM2-Lyz2-cre mice to validate the role of TREM2 signaling pathway in lung carcinogenesis. GB1107 were further supplemented to validate the therapeutic effect of Galectin3 based on TREM2 signaling regulation.
This study identified that abundant TREM2 macrophages were recruited at the intra-tumor site through the CCL2-CCR2 chemotactic axis. Galectin-3 impaired TREM2-mediated phagocytosis and promoted the conversion of TREM2 macrophages to immunosuppressive TAMs with attenuated antigen presentation and co-stimulatory functions both in vitro both in vivo, and galectin-3 is a potential ligand for TREM2. Genetic and pharmacological blockade of TREM2 and galectin-3 significantly inhibited lung cancer progression in subcutaneous and orthotopic cancer models by remodeling the tumor immune microenvironment.
Our findings revealed a previously unknown association between galectin-3 and TREM2 in TAMs of lung cancer, and suggested simultaneous inhibition of galectin3 and TREM2 as potent therapeutic approach for lung cancer therapy.
肿瘤相关巨噬细胞（TAMs）的高浸润与肿瘤促进和免疫抑制有关。髓样细胞触发受体 2（TREM2）的表达已成为 TAMs 中关键的免疫抑制调节因子，然而，TREM2 表达的 TAMs 是如何被招募的，以及 TREM2 与之相互作用的配体是什么，从而介导免疫抑制尚不清楚。
使用流式细胞术和单细胞 RNA 测序分析 TREM2 的表达。通过质谱和免疫沉淀来鉴定与 TREM2 结合的蛋白。通过吞噬作用和共培养实验来探索 galectin3-TREM2 对体外功能的影响。建立 TREM2-Lyz2-cre 小鼠以验证 TREM2 信号通路在肺癌发生中的作用。进一步补充 GB1107 以验证基于 TREM2 信号调节的 Galectin3 的治疗效果。
本研究发现，通过 CCL2-CCR2 趋化轴，大量的 TREM2 巨噬细胞被招募到肿瘤内部位。Galectin-3 损害了 TREM2 介导的吞噬作用，并促进 TREM2 巨噬细胞向免疫抑制性 TAMs 转化，减弱了抗原呈递和共刺激功能，无论是在体外还是体内，Galectin-3 都是 TREM2 的潜在配体。通过重塑肿瘤免疫微环境，TREM2 和 galectin-3 的遗传和药理学阻断显著抑制了皮下和原位癌症模型中的肺癌进展。
我们的研究结果揭示了肺癌 TAMs 中 galectin-3 和 TREM2 之间以前未知的关联，并表明同时抑制 galectin3 和 TREM2 是肺癌治疗的一种有潜力的治疗方法。
