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已发表论文
Sirp-α 抗体通过调节肿瘤相关巨噬细胞中的 Akt1/Akt2 抑制肾细胞癌进展
Authors Hao J, Liu N, Huang X , Zhou H , Li H, Zhang Y, Yu B, Bi Z, Song X, Li S, Chen K, Li N, Zhu C, Wang J
Received 27 March 2025
Accepted for publication 10 September 2025
Published 1 October 2025 Volume 2025:18 Pages 13575—13592
DOI https://doi.org/10.2147/JIR.S530775
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Dr Wenjian Li
Junfeng Hao,1,2,* Naiquan Liu,3,* Xin Huang,1,* Hanlei Zhou,3 Hanrong Li,4 Yizhou Zhang,4 Bing Yu,5 Ziqian Bi,6 Xinyuan Song,7 Shunan Li,8 Keyu Chen,9 Ning Li,10 Chao Zhu,11 Jiahe Wang1
1Department of Family Medicine, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China; 2Department of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, People’s Republic of China; 3Department of Nephrology, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China; 4Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China; 5Department of Medical Imaging, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China; 6Faculty of Information Technology, Beijing University of Technology, Beijing, People’s Republic of China; 7School of Physics, Peking University, Beijing, People’s Republic of China; 8BeeMI, Saint Louis, MO, USA; 9Georgia Institute of Technology, GA, USA; 10Yuqing Hemodialysis Service Management Group Co., Ltd, Shenyang, People’s Republic of China; 11Department of Rheumatology and Immunology, The Third Affiliated Hospital of Naval Medical University, Shanghai, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Chao Zhu, Department of Rheumatology and Immunology, The Third Affiliated Hospital of Naval Medical University, Shanghai, 201805, People’s Republic of China, Email zhuchaokidney@163.com Jiahe Wang, Department of Family Medicine, Shengjing Hospital of China Medical University, Shenyang, 110022, People’s Republic of China, Email wangjh1@sj-hospital.org
Introduction and Aim: Immunotherapies targeting tumor-associated macrophages (TAM) to improve antitumor immunity, are promising treatment strategies for many types of cancer. The signal-regulatory protein-α (Sirp-α)/CD47 axis is a key innate immune checkpoint target important in regulating phagocytosis in macrophages. We aimed to determine whether a Sirp-α monoclonal antibody (mAb) could prevent renal cell carcinoma (RCC) progression by acting on macrophages and modifying their phenotype.
Methods: We explored the gene expression signature of macrophages in the RCC microenvironment by analyzing transcriptome data of blood monocytes from patients with RCC vs healthy donors, and macrophages vs non-immune cells in RCC from public databases. We characterized the prevailing macrophage polarization phenotypes and the different ratios of Akt1 and Akt2 in RCC according to cell surface markers and expression profiles, prior to examining the effect of Sirp-α mAb on the M2 macrophage polarization in an in vitro co-culture model of RCC cells with macrophages. The co-culture model included human RCC cell lines and induced M2 macrophages, including a subset that had been transfected to overexpress phosphoinositide 3-kinase (PI3K).
Results and Conclusion: Treatment of RCC with Sirp-α mAb counteracted the enhanced migration and invasion of RCC as measured in wound healing and transwell assays and in vivo model. Collectively, our data showed that the different ratio of Akt1 and Akt2 of the PI3K/Akt pathway is involved in the RCC-induced M2 polarization of macrophages and that a new mechanism that the Sirp-α mAb inhibited M2 macrophage polarization by regulating components of the PI3K/Akt pathway. Elucidating the mechanism by which Sirp-α mAb inhibits the development of RCC allows us to provide a new theoretical basis for the study of the mAb in RCC immunotherapy.
Keywords: Sirp-α, renal cell carcinoma, macrophage, immune checkpoint, PI3K/Akt pathway
1Department of Family Medicine, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China; 2Department of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, People’s Republic of China; 3Department of Nephrology, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China; 4Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China; 5Department of Medical Imaging, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China; 6Faculty of Information Technology, Beijing University of Technology, Beijing, People’s Republic of China; 7School of Physics, Peking University, Beijing, People’s Republic of China; 8BeeMI, Saint Louis, MO, USA; 9Georgia Institute of Technology, GA, USA; 10Yuqing Hemodialysis Service Management Group Co., Ltd, Shenyang, People’s Republic of China; 11Department of Rheumatology and Immunology, The Third Affiliated Hospital of Naval Medical University, Shanghai, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Chao Zhu, Department of Rheumatology and Immunology, The Third Affiliated Hospital of Naval Medical University, Shanghai, 201805, People’s Republic of China, Email zhuchaokidney@163.com Jiahe Wang, Department of Family Medicine, Shengjing Hospital of China Medical University, Shenyang, 110022, People’s Republic of China, Email wangjh1@sj-hospital.org
Introduction and Aim: Immunotherapies targeting tumor-associated macrophages (TAM) to improve antitumor immunity, are promising treatment strategies for many types of cancer. The signal-regulatory protein-α (Sirp-α)/CD47 axis is a key innate immune checkpoint target important in regulating phagocytosis in macrophages. We aimed to determine whether a Sirp-α monoclonal antibody (mAb) could prevent renal cell carcinoma (RCC) progression by acting on macrophages and modifying their phenotype.
Methods: We explored the gene expression signature of macrophages in the RCC microenvironment by analyzing transcriptome data of blood monocytes from patients with RCC vs healthy donors, and macrophages vs non-immune cells in RCC from public databases. We characterized the prevailing macrophage polarization phenotypes and the different ratios of Akt1 and Akt2 in RCC according to cell surface markers and expression profiles, prior to examining the effect of Sirp-α mAb on the M2 macrophage polarization in an in vitro co-culture model of RCC cells with macrophages. The co-culture model included human RCC cell lines and induced M2 macrophages, including a subset that had been transfected to overexpress phosphoinositide 3-kinase (PI3K).
Results and Conclusion: Treatment of RCC with Sirp-α mAb counteracted the enhanced migration and invasion of RCC as measured in wound healing and transwell assays and in vivo model. Collectively, our data showed that the different ratio of Akt1 and Akt2 of the PI3K/Akt pathway is involved in the RCC-induced M2 polarization of macrophages and that a new mechanism that the Sirp-α mAb inhibited M2 macrophage polarization by regulating components of the PI3K/Akt pathway. Elucidating the mechanism by which Sirp-α mAb inhibits the development of RCC allows us to provide a new theoretical basis for the study of the mAb in RCC immunotherapy.
Keywords: Sirp-α, renal cell carcinoma, macrophage, immune checkpoint, PI3K/Akt pathway