{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T10:10:06Z","timestamp":1756289406578,"version":"3.44.0"},"reference-count":32,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T00:00:00Z","timestamp":1750896000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["eJHaem"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Immune checkpoint (IC) pathways, including programmed death protein 1 (PD\u20101), its ligand PD\u2010L1, and CTLA\u20104, mediate negative regulatory signals in immune responses. Recent studies in autoimmune diseases and malignancies reported that the presence of the soluble form of these ICs would reflect the overall immune status. We assessed the clinical significance of these soluble\u2010form ICs in HTLV\u20101 carriers and adult T\u2010cell leukemia\u2010lymphoma (ATL) patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>After obtaining informed consent, plasma from HTLV\u20101 carriers and ATL patients was prospectively collected in participating centers. Plasma concentrations of soluble\u2010form PD\u20101, PD\u2010L1, and CTLA\u20104 (sPD\u20101, sPD\u2010L1, and sCTLA\u20104) were measured.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Ninety\u2010six cases were included (HTLV\u20101 carriers, <jats:italic>n<\/jats:italic> = 4; indolent ATL, <jats:italic>n<\/jats:italic> = 14; aggressive ATL, <jats:italic>n<\/jats:italic> = 78). The median age at sampling was 65.5 (range, 23\u201385) years. Soluble factors levels were significantly higher in aggressive ATL than in indolent ATL (sPD\u20101, <jats:italic>p<\/jats:italic> = 0.003; sPD\u2010L1, <jats:italic>p<\/jats:italic> = 0.017; sCTLA\u20104, <jats:italic>p<\/jats:italic> &lt; 0.001). These markers were strongly correlated with soluble IL\u20102R (sPD\u20101, <jats:italic>r<\/jats:italic> = 0.80; sPD\u2010L1, <jats:italic>r<\/jats:italic> = 0.61; sCTLA\u20104, <jats:italic>r<\/jats:italic> = 0.82). Elevated soluble IC levels were significant adverse prognostic factors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Soluble IC levels were significantly higher in aggressive ATL than in indolent ATL, and predicted an adverse prognosis. Their clinical significance should be investigated in larger studies.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jha2.70046","type":"journal-article","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T13:41:17Z","timestamp":1750945277000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical Significance of Elevated Levels of Soluble\u2010Form Immune Checkpoint Molecules in Patients With Aggressive Adult T\u2010Cell Leukemia\u2010Lymphoma"],"prefix":"10.1002","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5118-7950","authenticated-orcid":false,"given":"Shigeo","family":"Fuji","sequence":"first","affiliation":[{"name":"Department of Hematology Osaka International Cancer Institute  Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junya","family":"Makiyama","sequence":"additional","affiliation":[{"name":"Department of Hematology Sasebo City General Hospital  Nagasaki Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3012-033X","authenticated-orcid":false,"given":"Kuniko","family":"Takano","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology &amp; Hematology Faculty of Medicine Oita University  Oita Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilseung","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Hematology Kyushu Cancer Center  Fukuoka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeo","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Medical &amp; Scientific Affairs, Sysmex Corporation  Kobe Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chihiro","family":"Suminaka","sequence":"additional","affiliation":[{"name":"Central Research Laboratories Sysmex Corporation  Kobe Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mao","family":"Kuroishi","sequence":"additional","affiliation":[{"name":"Central Research Laboratories Sysmex Corporation  Kobe Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yosuke","family":"Iwasaki","sequence":"additional","affiliation":[{"name":"Department of Medical &amp; Scientific Affairs, Sysmex Corporation  Kobe Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hidenori","family":"Kasahara","sequence":"additional","affiliation":[{"name":"Department of Hematology Osaka International Cancer Institute  Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuma","family":"Tada","sequence":"additional","affiliation":[{"name":"Department of Hematology Osaka International Cancer Institute  Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuhiro","family":"Shingai","sequence":"additional","affiliation":[{"name":"Department of Hematology Osaka International Cancer Institute  Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sayako","family":"Yuda","sequence":"additional","affiliation":[{"name":"Department of Hematology Osaka International Cancer Institute  Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takafumi","family":"Yokota","sequence":"additional","affiliation":[{"name":"Department of Hematology Osaka International Cancer Institute  Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Ishikawa","sequence":"additional","affiliation":[{"name":"Department of Hematology Osaka International Cancer Institute  Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,6,26]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3405"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.12380"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.108"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-02-698936"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00277-020-03967-x"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00277-022-04760-8"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.827921"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13123034"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.587460"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0264-y"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-018-0449-0"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/hon.2542"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/ejh.13621"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2014.137"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1080\/16078454.2019.1590965"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/hon.2636"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.17362"},{"issue":"12","key":"e_1_2_9_19_1","first-page":"4498","article-title":"Clinical Significance of Circulating Exosomal PD\u2010L1 and Soluble PD\u2010L1 in Extranodal NK\/T\u2010Cell Lymphoma, Nasal\u2010Type","volume":"10","author":"Li J. 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