{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:58:32Z","timestamp":1792789112566,"version":"4.5.0"},"reference-count":60,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T00:00:00Z","timestamp":1745971200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Council","award":["NSTC 112-2314-B-705-001"],"award-info":[{"award-number":["NSTC 112-2314-B-705-001"]}]},{"name":"National Science and Technology Council","award":["R109-39"],"award-info":[{"award-number":["R109-39"]}]},{"DOI":"10.13039\/501100012537","name":"Ditmanson Medical Foundation Chia-Yi Christian Hospital","doi-asserted-by":"publisher","award":["NSTC 112-2314-B-705-001"],"award-info":[{"award-number":["NSTC 112-2314-B-705-001"]}],"id":[{"id":"10.13039\/501100012537","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012537","name":"Ditmanson Medical Foundation Chia-Yi Christian Hospital","doi-asserted-by":"publisher","award":["R109-39"],"award-info":[{"award-number":["R109-39"]}],"id":[{"id":"10.13039\/501100012537","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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+ T and CD8+ 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+ 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.<\/jats:p>","DOI":"10.3390\/cells14090660","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T11:35:13Z","timestamp":1746185713000},"page":"660","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Immunosuppression of Tumor-Derived Factors Modulated Neutrophils in Upper Tract Urothelial Carcinoma Through Upregulation of Arginase-1 via ApoA1-STAT3 Axis"],"prefix":"10.3390","volume":"14","author":[{"given":"Chih-Chia","family":"Chang","sequence":"first","affiliation":[{"name":"Department of Radiation Therapy and Oncology, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi 60002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Bin","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Urology, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi 60002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0058-5128","authenticated-orcid":false,"given":"Cheng-Huang","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Urology, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi 60002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9139-5508","authenticated-orcid":false,"given":"Ming-Yang","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi 60002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeong-Chin","family":"Jou","sequence":"additional","affiliation":[{"name":"Department of Urology, St. Martin De Porres Hospital, Chiayi 60069, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Liang","family":"Tung","sequence":"additional","affiliation":[{"name":"Department of Pathology, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi 60002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Hong","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Urology, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi 60002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi-Feng","family":"Hung","sequence":"additional","affiliation":[{"name":"Department of Urology, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi 60002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meilin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya-Yan","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pi-Che","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Urology, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi 60002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6050-185X","authenticated-orcid":false,"given":"Shu-Fen","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, and Epigenomics Human Disease Research Center, National Chung Cheng University, Chiayi 62102, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"216318","DOI":"10.1016\/j.canlet.2023.216318","article-title":"The opportunities and challenges in immunotherapy: Insights from the regulation of PD-L1 in cancer cells","volume":"569","author":"Lin","year":"2023","journal-title":"Cancer Lett."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/s41577-020-0306-5","article-title":"A guide to cancer immunotherapy: From T cell basic science to clinical practice","volume":"20","author":"Waldman","year":"2020","journal-title":"Nat. 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