2. Academic Validation
  3. C/EBPα mediates the maturation and antitumor functions of macrophages in human hepatocellular carcinoma

C/EBPα mediates the maturation and antitumor functions of macrophages in human hepatocellular carcinoma

  • Cancer Lett. 2024 Mar 31:585:216638. doi: 10.1016/j.canlet.2024.216638.
Yongchun Wang 1,  Zhixiong Li 2,  Weibai Chen 1,  Junfeng Wang 2,  Zhijie Huang 2,  Xing-Juan Yu 2,  Yao-Jun Zhang 3,  Limin Zheng 4,  Jing Xu 5
Affiliations

Affiliations

  • 1 Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China; Key Laboratory of Gene Function and Regulation of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China.
  • 2 Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
  • 3 Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China; Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
  • 4 Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China; Key Laboratory of Gene Function and Regulation of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China. Electronic address: zhenglm@mail.sysu.edu.cn.
  • 5 Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China. Electronic address: xujing@sysucc.org.cn.
PMID: 38266805 DOI: 10.1016/j.canlet.2024.216638
Abstract

Recent studies have suggested that therapeutic upregulation of CCAAT/enhancer binding protein α (C/EBPα) prevents hepatocellular carcinoma (HCC) progression. However, the mechanisms underlying this outcome are not fully understood. In this study, we investigated the expression and functional roles of C/EBPα in human HCC, with a focus on monocytes/macrophages (Mφs). Paraffin-embedded tissues were used to visualize C/EBPα expression and analyze the prognostic value of C/EBPα+ monocytes/Mφs in HCC patients. The underlying regulatory mechanisms were examined using human monocyte-derived Mφs. The results showed that the expression of C/EBPα on monocytes/Mφs was significantly decreased in intra-tumor tissues compared to the corresponding peri-tumor tissues. C/EBPα+ monocytes/Mφs displayed well-differentiation and antitumor capacities, and the accumulation of these cells in tissue was associated with antitumor immune responses and predicted longer overall survival (OS) of HCC patients. Mechanistic studies demonstrated that C/EBPα was required for Mφ maturation and HLA-DR, CD169 and CD86 expression, which initiates antitumor cytotoxic T-cell responses; however, these effects were inhibited by monocyte autocrine IL-6- and IL-1β-induced suppression of mTOR1 signaling. Reprogramming Mφs via the upregulation of C/EBPα may provide a novel strategy for Cancer Immunotherapy in patients with HCC.

Keywords

C/EBPα; Hepatocellular carcinoma; Macrophage maturation; Prognosis; mTOR1.

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