组织定居的CXCR4+巨噬细胞作为不良预后标志物，促进胰管腺癌的进展。
Tissue-resident CXCR4+ macrophage as a poor prognosis signature promotes pancreatic ductal adenocarcinoma progression.
发表日期：2023 Feb 09
作者：
Zhenyu Liao, Longyun Ye, Tianjiao Li, Xing Jin, Xuan Lin, Qinglin Fei, Huiru Zhang, Saimeng Shi, Xianjun Yu, Kaizhou Jin, Weiding Wu
来源：
INTERNATIONAL JOURNAL OF CANCER
摘要：
巨噬细胞是胰腺导管腺癌肿瘤免疫微环境中的重要组成部分。在我们的研究中，我们探讨了CXCR4+巨噬细胞亚群在胰腺癌进展中的预后价值、免疫特性和不同功能。对102名手术后的胰腺癌患者标本进行流式细胞术或免疫荧光分析，并通过Cox回归进一步确定CXCR4+巨噬细胞浸润的预后价值。对TCGA、ICGC数据库和胰腺导管腺癌单细胞测序的体外分析进一步验证了我们的发现。我们发现高水平的CXCR4+巨噬细胞浸润与总生存率（P < .01）和无病生存率（P < .05）显著相关。CXCR4+巨噬细胞表现出高表达CD206的M2原肿瘤表型。在小鼠原位PDAC模型中进一步分析了CXCR4+巨噬细胞的功能，证明其对肿瘤的促进作用和对CD8+T细胞的抑制作用。机制和RNA-seq分析显示，CXCR4+巨噬细胞参与了细胞外基质重塑过程，特别是通过CXCR4 / PI3K / Akt通路分泌SPARC促进肿瘤增殖和迁移。我们的研究揭示了CXCR4+巨噬细胞浸润是PDAC不良预后的指标，靶向这些细胞在PDAC免疫治疗中具有重要意义。 ©2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
Macrophage is an essential part of the tumor immune microenvironment of pancreatic ductal adenocarcinoma. In our study, we explored the CXCR4+ macrophages subset on its prognosis value, immune profile and distinct function in pancreatic cancer progression. Specimens from 102 postoperative pancreatic patients were analyzed by flow cytometry or immune-fluorescence, and the prognostic value of CXCR4+ macrophages infiltration was further determined by Cox regression. In silico analysis on TCGA, ICGC database and single-cell sequencing of pancreatic ductal adenocarcinoma further validated our findings. We found that high CXCR4+ macrophages infiltration was associated with poor overall survival (P < .01) and disease-free survival (P < .05) as an independent factor. CXCR4+ macrophages exhibited an M2 protumor phenotype with high expression of CD206. The function of CXCR4+ macrophages was further analyzed in the murine orthotopic PDAC model with its tumor promotion effect and inhibition of CD8+ T cells. Mechanistic and RNA-seq analysis showed that CXCR4+ macrophages participated in extracellular matrix remodeling procedures and especially secreted SPARC through CXCR4/PI3K/Akt pathway promoting tumor proliferation and migration. Our study reveals that CXCR4+ macrophages infiltration is an indicator of poor prognosis of PDAC and targeting these cells was potentially crucial in immunotherapy of PDAC.© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.