{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T10:24:50Z","timestamp":1790677490693,"version":"4.1.0"},"reference-count":36,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2024,2,27]],"date-time":"2024-02-27T00:00:00Z","timestamp":1708992000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2024,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Hypoxia is a common feature of solid tumors. However, the impact of hypoxia on immune cells within tumor environments remains underexplored. Carbonic anhydrase 9 (CA9) is a hypoxia\u2010responsive tumor\u2010associated enzyme. We previously noted that regardless of human CA9 (hCA9) expression, hCA9\u2010expressing mouse renal cell carcinoma RENCA (RENCA\/hCA9) presented as a \u201ccold\u201d tumor in syngeneic aged mice. This study delves into the mechanisms behind this observation. Gene microarray analyses showed that RENCA\/hCA9 cells exhibited elevated mouse serpinB9, an inhibitor of granzyme B, relative to RENCA cells. Corroborating this, RENCA\/hCA9 cells displayed heightened resistance to antigen\u2010specific cytotoxic T cells compared with RENCA cells. Notably, siRNA\u2010mediated serpinB9 knockdown reclaimed this sensitivity. In\u00a0vivo tests showed that serpinB9 inhibitor administration slowed RENCA tumor growth, but this effect was reduced in RENCA\/hCA9 tumors, even with adjunctive immune checkpoint blockade therapy. Further, inducing hypoxia or introducing the mouse\n                    <jats:italic>CA9<\/jats:italic>\n                    gene upregulated serpinB9 expression, and siRNA\u2010mediated knockdown of the mouse\n                    <jats:italic>CA9<\/jats:italic>\n                    gene inhibited the hypoxia\u2010induced induction of serpinB9 in the original RENCA cells. Supernatants from RENCA\/hCA9 cultures had lower pH than those from RENCA, suggesting acidosis. This acidity enhanced serpinB9 expression and T cell apoptosis. Moreover, coculturing with RENCA\/hCA9 cells more actively prompted T cell apoptosis than with RENCA cells. Collectively, these findings suggest hypoxia\u2010associated CA9 not only boosts serpinB9 in cancer cells but also synergistically intensifies T cell apoptosis via acidosis, characterizing RENCA\/hCA9 tumors as \u201ccold.\u201d\n                  <\/jats:p>","DOI":"10.1111\/cas.16133","type":"journal-article","created":{"date-parts":[[2024,2,27]],"date-time":"2024-02-27T22:00:42Z","timestamp":1709071242000},"page":"1405-1416","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Hypoxia\u2010related carbonic anhydrase 9 induces\n                    <scp>serpinB9<\/scp>\n                    expression in cancer cells and apoptosis in T cells via acidosis"],"prefix":"10.1111","volume":"115","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9737-0360","authenticated-orcid":false,"given":"Mamoru","family":"Harada","sequence":"first","affiliation":[{"name":"Department of Immunology Shimane University Faculty of Medicine  Shimane Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Kotani","sequence":"additional","affiliation":[{"name":"Department of Immunology Shimane University Faculty of Medicine  Shimane Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Iida","sequence":"additional","affiliation":[{"name":"Department of Immunology Shimane University Faculty of Medicine  Shimane Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5148-9526","authenticated-orcid":false,"given":"Ryosuke","family":"Tanino","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology &amp; Respiratory Medicine, Department of Internal Medicine Shimane University Faculty of Medicine  Shimane Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takafumi","family":"Minami","sequence":"additional","affiliation":[{"name":"Department of Urology Kindai University Faculty of Medicine  Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9723-0846","authenticated-orcid":false,"given":"Yoshihiro","family":"Komohara","sequence":"additional","affiliation":[{"name":"Department of Cell Pathology, Graduate School of Medical Science Kumamoto University  Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Yoshikawa","sequence":"additional","affiliation":[{"name":"Research Creation Support Center Aichi Medical University  Aichi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3665-9523","authenticated-orcid":false,"given":"Hirotsugu","family":"Uemura","sequence":"additional","affiliation":[{"name":"Department of Urology Kindai University Faculty of Medicine  Osaka 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