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揭示通过RGS2/PAR2途径由CEBPD精心调控的肿瘤相关巨噬细胞极化机制及其对透明细胞肾细胞癌免疫检查点阻断疗效的影响。

Unveiling the mechanisms of CEBPD-orchestrated TAM polarization through RGS2/PAR2 pathway and its impact on ICB efficacy in clear cell renal cell carcinoma.

作者信息

Pan Xiu-Wu, Zheng Hong-Feng, Li Mu-Chen, Dong Ke-Qin, Tang Yi-Fan, Chen Jia-Xin, Yang Tian-Yue, Liu Jian-Gui, Liu Zi-Chang, Liu Yifan, Li Wen-Yan, Gong Zi-Xuan, Zhang Shun, Zhou Wang, Gu Jun, Cui Xin-Gang

机构信息

Department of Urology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.

Department of Urology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China

出版信息

J Immunother Cancer. 2025 Jul 13;13(7):e010898. doi: 10.1136/jitc-2024-010898.

DOI:10.1136/jitc-2024-010898
PMID:40659446
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12258302/
Abstract

BACKGROUND

The polarization status and function of tumor-associated macrophages (TAMs) influence tumor progression and patients' prognosis. CCAAT/enhancer-binding proteins (CEBPs) family are important transcriptional factors in macrophages differentiation physically and pathologically. This study aims to explore the mechanism of CEBPs in TAMs polarization in clear cell renal cell carcinoma (ccRCC) immune microenvironment and its impact on immune checkpoint blockers (ICBs) therapy.

METHODS

The expression of CEBPs in ccRCC was analyzed by single-cell transcriptome and western blot. Immunofluorescence and in-vitro polarization assay were used to evaluate the effect of CEBP delta (CEBPD) on TAMs. Chromatin immunoprecipitation sequencing was used to explore targets of CEBPD. Dual-luciferase reporter assay and electrophoretic mobility shift assay were performed to confirm the regulation of CEBPD to RGS2. Specimens of patients received ICB therapy were used to analyze the relationship between CEBPD and immunotherapy.

RESULTS

The study identified CEBPD as a key transcriptional factor in ccRCC TAM polarization. Upregulation of CEBPD correlates to decreased M1/M2 ratio of TAMs and poorer clinical outcomes. CEBPD inhibited M1-like polarization in vitro and in vivo via the RGS2/PAR2 axis. Furthermore, CEBPD also affected the therapeutic efficacy of ICB.

CONCLUSION

This study revealed CEBPD regulated TAM polarization via the CEBPD/RGS2/PAR2 axis. Targeting CEBPD may be a potential approach and a complementary strategy to ICB therapies in ccRCC.

摘要

背景

肿瘤相关巨噬细胞（TAM）的极化状态和功能影响肿瘤进展及患者预后。CCAAT/增强子结合蛋白（CEBP）家族是巨噬细胞在生理和病理分化过程中的重要转录因子。本研究旨在探讨CEBP在透明细胞肾细胞癌（ccRCC）免疫微环境中TAM极化的机制及其对免疫检查点阻断剂（ICB）治疗的影响。

方法

通过单细胞转录组和蛋白质免疫印迹分析ccRCC中CEBP的表达。采用免疫荧光和体外极化实验评估CEBPδ（CEBPD）对TAM的作用。利用染色质免疫沉淀测序探索CEBPD的靶标。进行双荧光素酶报告基因检测和电泳迁移率变动分析以证实CEBPD对RGS2的调控。使用接受ICB治疗患者的标本分析CEBPD与免疫治疗之间的关系。

结果

该研究确定CEBPD是ccRCC中TAM极化的关键转录因子。CEBPD的上调与TAM的M1/M2比值降低及较差的临床预后相关。CEBPD在体外和体内通过RGS2/PAR2轴抑制M1样极化。此外，CEBPD还影响ICB的治疗效果。

结论

本研究揭示CEBPD通过CEBPD/RGS2/PAR2轴调节TAM极化。靶向CEBPD可能是ccRCC中ICB治疗的一种潜在方法和补充策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90e3/12258302/79a7b299b886/jitc-13-7-g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90e3/12258302/cdd8c68a8862/jitc-13-7-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90e3/12258302/03e7a143f8ac/jitc-13-7-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90e3/12258302/8cf0c6b78151/jitc-13-7-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90e3/12258302/79a7b299b886/jitc-13-7-g008.jpg

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本文引用的文献

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Tumor-associated macrophage enhances PD-L1-mediated immune escape of bladder cancer through PKM2 dimer-STAT3 complex nuclear translocation.肿瘤相关巨噬细胞通过 PKM2 二聚体-STAT3 复合物核转位增强膀胱癌中 PD-L1 介导的免疫逃逸。
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VDR promotes pancreatic cancer progression in vivo by activating CCL20-mediated M2 polarization of tumor associated macrophage.
VDR 通过激活 CCL20 介导的肿瘤相关巨噬细胞 M2 极化促进体内胰腺癌的进展。
Cell Commun Signal. 2024 Apr 10;22(1):224. doi: 10.1186/s12964-024-01578-x.
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Single-cell analysis of immune and stroma cell remodeling in clear cell renal cell carcinoma primary tumors and bone metastatic lesions.单细胞分析透明细胞肾细胞癌原发肿瘤和骨转移病变中的免疫和基质细胞重塑。
Genome Med. 2024 Jan 29;16(1):1. doi: 10.1186/s13073-023-01272-6.
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Vinblastine resets tumor-associated macrophages toward M1 phenotype and promotes antitumor immune response.长春碱将肿瘤相关巨噬细胞重置为 M1 表型，并促进抗肿瘤免疫反应。
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Macrophages in immunoregulation and therapeutics.巨噬细胞在免疫调节和治疗中的作用。
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