Immunosuppression of Tumor-Derived Factors Modulated Neutrophils in Upper Tract Urothelial Carcinoma Through Upregulation of Arginase-1 via ApoA1-STAT3 Axis
Upper tract urothelial carcinoma (UTUC) presents aggressive features and a tumor microenvironment with T cell depletion. However, the role of tumor-associated neutrophils in UTUC remains unclear. This study aimed to investigate how UTUC tumor-derived factors modulate neutrophils and their impact on...
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2025-04-01
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| author | Chih-Chia Chang Chia-Bin Chang Cheng-Huang Shen Ming-Yang Lee Yeong-Chin Jou Chun-Liang Tung Wei-Hong Lai Chi-Feng Hung Meilin Wang Ya-Yan Lai Pi-Che Chen Shu-Fen Wu |
| author_facet | Chih-Chia Chang Chia-Bin Chang Cheng-Huang Shen Ming-Yang Lee Yeong-Chin Jou Chun-Liang Tung Wei-Hong Lai Chi-Feng Hung Meilin Wang Ya-Yan Lai Pi-Che Chen Shu-Fen Wu |
| author_sort | Chih-Chia Chang |
| collection | DOAJ |
| description | Upper tract urothelial carcinoma (UTUC) presents aggressive features and a tumor microenvironment with T cell depletion. However, the role of tumor-associated neutrophils in UTUC remains unclear. This study aimed to investigate how UTUC tumor-derived factors modulate neutrophils and their impact on T cell immune responses. Our findings demonstrate that UTUC secreted tumor-derived factors, with apolipoprotein A1 (Apo-A1) being the predominant factor, which upregulated arginase-1 expression in neutrophils. STAT3 activation was responsible for the upregulation of arginase-1 in neutrophils. Blocking the interactions between Apo-A1 and its receptors reduced arginase-1 expression in neutrophils treated with tumor tissue culture supernatant (TTCS). Moreover, both CD4<sup>+</sup> T and CD8<sup>+</sup> T cell proliferation were inhibited by neutrophils treated with Apo-A1 or TTCS. Importantly, blocking Apo-A1 signaling in neutrophils reversed the inhibitory effects on T cells. In UTUC patients, the neutrophil-to-lymphocyte ratio was higher than that in healthy subjects. The expression of arginase-1 in neutrophils and the level of Apo-A1 within UTUC tumors were negatively correlated with tumor-infiltrating CD4<sup>+</sup> T cells. Additionally, neutrophils from UTUC patients showed increased expression of arginase-1 and exhibited inhibitory effects of T cell functions. These findings suggest that UTUC orchestrates an immune-suppressive microenvironment through Apo-A1-mediated upregulation of arginase-1 in neutrophils, ultimately leading to the inhibition of T cell proliferation. |
| format | Article |
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| issn | 2073-4409 |
| language | English |
| publishDate | 2025-04-01 |
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| spelling | doaj-art-b389135a70ed437d95f0fda0b97fb8d92025-08-20T01:49:14ZengMDPI AGCells2073-44092025-04-0114966010.3390/cells14090660Immunosuppression of Tumor-Derived Factors Modulated Neutrophils in Upper Tract Urothelial Carcinoma Through Upregulation of Arginase-1 via ApoA1-STAT3 AxisChih-Chia Chang0Chia-Bin Chang1Cheng-Huang Shen2Ming-Yang Lee3Yeong-Chin Jou4Chun-Liang Tung5Wei-Hong Lai6Chi-Feng Hung7Meilin Wang8Ya-Yan Lai9Pi-Che Chen10Shu-Fen Wu11Department of Radiation Therapy and Oncology, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi 60002, TaiwanDepartment of Urology, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi 60002, TaiwanDepartment of Urology, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi 60002, TaiwanDepartment of Hematology and Oncology, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi 60002, TaiwanDepartment of Urology, St. Martin De Porres Hospital, Chiayi 60069, TaiwanDepartment of Pathology, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi 60002, TaiwanDepartment of Urology, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi 60002, TaiwanDepartment of Urology, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi 60002, TaiwanDepartment of Microbiology and Immunology, School of Medicine, Chung Shan Medical University, Taichung 40201, TaiwanDepartment of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, TaiwanDepartment of Urology, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi 60002, TaiwanDepartment of Biomedical Sciences, and Epigenomics Human Disease Research Center, National Chung Cheng University, Chiayi 62102, TaiwanUpper tract urothelial carcinoma (UTUC) presents aggressive features and a tumor microenvironment with T cell depletion. However, the role of tumor-associated neutrophils in UTUC remains unclear. This study aimed to investigate how UTUC tumor-derived factors modulate neutrophils and their impact on T cell immune responses. Our findings demonstrate that UTUC secreted tumor-derived factors, with apolipoprotein A1 (Apo-A1) being the predominant factor, which upregulated arginase-1 expression in neutrophils. STAT3 activation was responsible for the upregulation of arginase-1 in neutrophils. Blocking the interactions between Apo-A1 and its receptors reduced arginase-1 expression in neutrophils treated with tumor tissue culture supernatant (TTCS). Moreover, both CD4<sup>+</sup> T and CD8<sup>+</sup> T cell proliferation were inhibited by neutrophils treated with Apo-A1 or TTCS. Importantly, blocking Apo-A1 signaling in neutrophils reversed the inhibitory effects on T cells. In UTUC patients, the neutrophil-to-lymphocyte ratio was higher than that in healthy subjects. The expression of arginase-1 in neutrophils and the level of Apo-A1 within UTUC tumors were negatively correlated with tumor-infiltrating CD4<sup>+</sup> T cells. Additionally, neutrophils from UTUC patients showed increased expression of arginase-1 and exhibited inhibitory effects of T cell functions. These findings suggest that UTUC orchestrates an immune-suppressive microenvironment through Apo-A1-mediated upregulation of arginase-1 in neutrophils, ultimately leading to the inhibition of T cell proliferation.https://www.mdpi.com/2073-4409/14/9/660upper tract urothelial carcinomatumor tissue culture supernatantneutrophilsarginase-1T cells |
| spellingShingle | Chih-Chia Chang Chia-Bin Chang Cheng-Huang Shen Ming-Yang Lee Yeong-Chin Jou Chun-Liang Tung Wei-Hong Lai Chi-Feng Hung Meilin Wang Ya-Yan Lai Pi-Che Chen Shu-Fen Wu Immunosuppression of Tumor-Derived Factors Modulated Neutrophils in Upper Tract Urothelial Carcinoma Through Upregulation of Arginase-1 via ApoA1-STAT3 Axis Cells upper tract urothelial carcinoma tumor tissue culture supernatant neutrophils arginase-1 T cells |
| title | Immunosuppression of Tumor-Derived Factors Modulated Neutrophils in Upper Tract Urothelial Carcinoma Through Upregulation of Arginase-1 via ApoA1-STAT3 Axis |
| title_full | Immunosuppression of Tumor-Derived Factors Modulated Neutrophils in Upper Tract Urothelial Carcinoma Through Upregulation of Arginase-1 via ApoA1-STAT3 Axis |
| title_fullStr | Immunosuppression of Tumor-Derived Factors Modulated Neutrophils in Upper Tract Urothelial Carcinoma Through Upregulation of Arginase-1 via ApoA1-STAT3 Axis |
| title_full_unstemmed | Immunosuppression of Tumor-Derived Factors Modulated Neutrophils in Upper Tract Urothelial Carcinoma Through Upregulation of Arginase-1 via ApoA1-STAT3 Axis |
| title_short | Immunosuppression of Tumor-Derived Factors Modulated Neutrophils in Upper Tract Urothelial Carcinoma Through Upregulation of Arginase-1 via ApoA1-STAT3 Axis |
| title_sort | immunosuppression of tumor derived factors modulated neutrophils in upper tract urothelial carcinoma through upregulation of arginase 1 via apoa1 stat3 axis |
| topic | upper tract urothelial carcinoma tumor tissue culture supernatant neutrophils arginase-1 T cells |
| url | https://www.mdpi.com/2073-4409/14/9/660 |
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