MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
Front Immunol. 2024 Nov 8;15:1481972. doi: 10.3389/fimmu.2024.1481972. eCollection 2024.
Sex hormones and their related receptors have been reported to impact the development and progression of tumors. However, their influence on the composition and function of the tumor microenvironment is not well understood. We aimed to investigate the influence of sex disparities on the proliferation and accumulation of macrophages, one of the major components of the tumor microenvironment, in hepatocellular carcinoma (HCC).
Immunohistochemistry was applied to assess the density of immune cells in HCC tissues. The role of sex hormone related signaling in macrophage proliferation was determined by immunofluorescence and flow cytometry. The underlying regulatory mechanisms were examined with both experiments and murine HCC models.
We found higher levels of macrophage proliferation and density in tumor tissues from male patients compared to females. The expression of G protein-coupled estrogen receptor 1 (GPER1), a non-classical estrogen receptor, was significantly decreased in proliferating macrophages, and was inversely correlated with macrophage proliferation in HCC tumors. Activation of GPER1 signaling with a selective agonist G-1 suppressed macrophage proliferation by downregulating the MEK/ERK pathway. Additionally, G-1 treatment reduced PD-L1 expression on macrophages and delayed tumor growth in mice. Moreover, patients with a higher percentage of GPER1 macrophages exhibited longer overall survival and recurrence-free survival compared to those with a lower level.
These findings reveal a novel role of GPER1 signaling in regulating macrophage proliferation and function in HCC tumors and may offer a potential strategy for designing therapies based on understanding sex-related disparities of patients.
性激素及其相关受体已被报道会影响肿瘤的发生和发展。然而，它们对肿瘤微环境的组成和功能的影响还不是很清楚。我们旨在研究性别差异对肝癌（HCC）中肿瘤微环境主要成分之一巨噬细胞的增殖和积累的影响。
免疫组织化学用于评估 HCC 组织中免疫细胞的密度。通过免疫荧光和流式细胞术确定性激素相关信号在巨噬细胞增殖中的作用。通过实验和鼠 HCC 模型研究了潜在的调节机制。
我们发现男性患者肿瘤组织中的巨噬细胞增殖和密度高于女性。增殖巨噬细胞中 G 蛋白偶联雌激素受体 1（GPER1）的表达明显降低，并且与 HCC 肿瘤中的巨噬细胞增殖呈负相关。用选择性激动剂 G-1 激活 GPER1 信号通路通过下调 MEK/ERK 通路抑制巨噬细胞增殖。此外，G-1 处理可降低巨噬细胞上的 PD-L1 表达并延缓小鼠肿瘤生长。此外，与 GPER1 巨噬细胞水平较低的患者相比，GPER1 巨噬细胞比例较高的患者总体生存率和无复发生存率更长。
这些发现揭示了 GPER1 信号在调节 HCC 肿瘤中巨噬细胞增殖和功能中的新作用，并可能为基于理解患者性别相关差异的治疗设计提供潜在策略。
