General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, Jiangsu, China.
General Clinical Research Center, Nanjing First Hospital, China Pharmaceutical University, Nanjing 210006, Jiangsu, China.
Carcinogenesis. 2024 Oct 10;45(10):745-758. doi: 10.1093/carcin/bgae058.
Tumor-associated macrophages (TAMs) take on pivotal and complex roles in the tumor microenvironment (TME); however, their heterogeneity in the TME remains incompletely understood. ETS proto-oncogene 1 (ETS1) is a transcription factor that is mainly expressed in lymphocytes. However, its expression and immunoregulatory role in colorectal cancer (CRC)-associated macrophages remain unclear. In the study, the expression levels of ETS1 in CD68+ macrophages in the CRC microenvironment were significantly higher than those in matched paracarcinoma tissues. Importantly, ETS1 increased the levels of chemokines C-C motif chemokine ligand 2 (CCL2) and C-X-C motif chemokine ligand 10 (CXCL10) in lipopolysaccharide-stimulated THP-1 cells. It also boosted the migration and invasion of CRC cells during the in vitro co-culture. In the ETS1 conditional knockout mouse model, ETS1 deficiency in macrophages ameliorated the histological changes in DSS-induced ulcerative colitis mouse models and prolonged the survival in an azomethane/dextran sodium sulfate (AOM/DSS)-induced CRC model. ETS1 deficiency in macrophages substantially inhibited tumor formation, reduced F4/80+TIM4+ macrophages in the mesenteric lymph nodes, and decreased CCL2 and CXCL10 protein levels in tumor tissues. Moreover, ETS1 deficiency in macrophages effectively prevented liver metastasis of CRC and reduced the infiltration of TAMs into the metastasis sites. Subsequent studies have indicated that ETS1 upregulated the expression of T-cell immunoglobulin mucin receptor 4 in macrophages through the signal transducer and activator of the transcription 1 signaling pathway activated by the autocrine action of CCL2/CXCL10. Collectively, ETS1 deficiency in macrophages potentiates antitumor immune responses by repressing CCL2 and CXCL10 expression, shedding light on potential therapeutic strategies for CRC.
肿瘤相关巨噬细胞（TAMs）在肿瘤微环境（TME）中发挥着关键而复杂的作用；然而，它们在 TME 中的异质性仍不完全清楚。ETS 原癌基因 1（ETS1）是一种主要在淋巴细胞中表达的转录因子。然而，其在结直肠癌（CRC）相关巨噬细胞中的表达和免疫调节作用尚不清楚。在这项研究中，CRC 微环境中 CD68+巨噬细胞中的 ETS1 表达水平明显高于配对癌旁组织。重要的是，ETS1 增加了脂多糖刺激的 THP-1 细胞中趋化因子 C-C 基序趋化因子配体 2（CCL2）和 C-X-C 基序趋化因子配体 10（CXCL10）的水平。它还促进了体外共培养过程中 CRC 细胞的迁移和侵袭。在 ETS1 条件性敲除小鼠模型中，巨噬细胞中 ETS1 的缺失改善了 DSS 诱导的溃疡性结肠炎小鼠模型中的组织学变化，并延长了在偶氮甲烷/葡聚糖硫酸钠（AOM/DSS）诱导的 CRC 模型中的生存时间。巨噬细胞中 ETS1 的缺失显著抑制肿瘤形成，减少肠系膜淋巴结中 F4/80+TIM4+巨噬细胞的数量，并降低肿瘤组织中 CCL2 和 CXCL10 蛋白水平。此外，巨噬细胞中 ETS1 的缺失有效防止了 CRC 的肝转移，并减少了 TAMs 向转移部位的浸润。随后的研究表明，ETS1 通过 CCL2/CXCL10 的自分泌作用激活信号转导和转录激活因子 1 信号通路，上调巨噬细胞中 T 细胞免疫球蛋白粘蛋白受体 4 的表达。综上所述，巨噬细胞中 ETS1 的缺失通过抑制 CCL2 和 CXCL10 的表达增强了抗肿瘤免疫反应，为 CRC 的潜在治疗策略提供了依据。
