{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:50:50Z","timestamp":1792651850879,"version":"4.5.0"},"reference-count":50,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T00:00:00Z","timestamp":1754265600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T00:00:00Z","timestamp":1754265600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP24ama221534"],"award-info":[{"award-number":["JP24ama221534"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP23ck0106860"],"award-info":[{"award-number":["JP23ck0106860"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP23fk0108672"],"award-info":[{"award-number":["JP23fk0108672"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"MEXT | Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP24K02317"],"award-info":[{"award-number":["JP24K02317"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"MEXT | Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP22K08386"],"award-info":[{"award-number":["JP22K08386"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"MEXT | Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP22H02987"],"award-info":[{"award-number":["JP22H02987"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"MEXT | Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP22H04923"],"award-info":[{"award-number":["JP22H04923"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"MEXT | Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP24KJ0953"],"award-info":[{"award-number":["JP24KJ0953"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Leukemia"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>In adult T-cell leukemia\/lymphoma (ATL), tumor cells show a regulatory T-cell (Treg)-type phenotype, which influences their tumor immunity. However, our knowledge of what molecular events are involved in pathogenesis is still missing. Here, we took advantage of this unique phenotype and screened whole transcriptome data from primary ATL cells to search for effective therapeutic targets. Glycoprotein A repetitions predominant (GARP) was identified as a novel tumor antigen in ATL. ATL cells overexpress GARP and release transforming growth factor-\u03b2 (TGF-\u03b2). The GARP\u2013TGF-\u03b2 axis promotes cell proliferation of ATL cells and human T-cell leukemia virus type 1 (HTLV-1)-infected cells with changes in cell signaling activities and shaping of Treg gene expression patterns, but suppresses the activity of surrounding effector T-cells. Remarkably, this study has provided a breakthrough therapeutic concept that achieves the dual effect of direct tumor cell depletion and indirect immune activation by a single treatment targeting GARP. DS-1055a, an anti-GARP monoclonal antibody, selectively and effectively depleted malignant ATL cells via antibody-dependent cellular cytotoxicity, supporting the proof-of-concept in the preclinical study. Our findings highlight the key to understanding the cell origin of ATL and developing unprecedented therapeutic strategies for refractory diseases.<\/jats:p>","DOI":"10.1038\/s41375-025-02725-0","type":"journal-article","created":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T21:31:07Z","timestamp":1754343067000},"page":"2465-2476","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Bidirectional anti-tumor and immunological strategies by targeting GARP\u2013TGF-\u03b2 axis in adult T-cell leukemia\/lymphoma"],"prefix":"10.1038","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-2781-3457","authenticated-orcid":false,"given":"Kako","family":"Suzuki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seina","family":"Kusayanagi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuta","family":"Kuze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masato","family":"Hata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiho","family":"Kozuma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2031-7385","authenticated-orcid":false,"given":"Koji","family":"Jimbo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6526-0992","authenticated-orcid":false,"given":"Yasuhito","family":"Nannya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaka","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaoru","family":"Uchimaru","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8142-4686","authenticated-orcid":false,"given":"Makoto","family":"Yamagishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,4]]},"reference":[{"key":"2725_CR1","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abi4613","volume":"7","author":"JM Moreau","year":"2022","unstructured":"Moreau JM, Velegraki M, Bolyard C, Rosenblum MD, Li Z. Transforming growth factor\u2013\u03b21 in regulatory T cell biology. Sci Immunol. 2022;7:eabi4613.","journal-title":"Sci Immunol"},{"key":"2725_CR2","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1038\/cr.2016.151","volume":"27","author":"A Tanaka","year":"2017","unstructured":"Tanaka A, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Cell Res. 2017;27:109\u201318.","journal-title":"Cell Res"},{"key":"2725_CR3","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2021.108469","volume":"104","author":"B-J Chen","year":"2022","unstructured":"Chen B-J, Zhao J-W, Zhang D-H, Zheng A-H, Wu G-Q. Immunotherapy of cancer by targeting regulatory T cells. Int Immunopharmacol. 2022;104:108469.","journal-title":"Int Immunopharmacol"},{"key":"2725_CR4","doi-asserted-by":"publisher","first-page":"2080","DOI":"10.1111\/cas.14069","volume":"110","author":"Y Ohue","year":"2019","unstructured":"Ohue Y, Nishikawa H. Regulatory T (Treg) cells in cancer: can Treg cells be a new therapeutic target?. Cancer Sci. 2019;110:2080\u20139.","journal-title":"Cancer Sci"},{"key":"2725_CR5","doi-asserted-by":"publisher","first-page":"322","DOI":"10.3389\/fmicb.2012.00322","volume":"3","author":"M Iwanaga","year":"2012","unstructured":"Iwanaga M, Watanabe T, Yamaguchi K. Adult T-cell leukemia: a review of epidemiological evidence. Front Microbiol. 2012;3:322.","journal-title":"Front Microbiol"},{"key":"2725_CR6","doi-asserted-by":"publisher","first-page":"4567","DOI":"10.1111\/cas.14658","volume":"111","author":"Y Imaizumi","year":"2020","unstructured":"Imaizumi Y, Iwanaga M, Nosaka K, Ishitsuka K, Ishizawa K, Ito S, et al. Prognosis of patients with adult T-cell leukemia\/lymphoma in Japan: a nationwide hospital-based study. Cancer Sci. 2020;111:4567\u201380.","journal-title":"Cancer Sci"},{"key":"2725_CR7","doi-asserted-by":"publisher","first-page":"1304","DOI":"10.1038\/ng.3415","volume":"47","author":"K Kataoka","year":"2015","unstructured":"Kataoka K, Nagata Y, Kitanaka A, Shiraishi Y, Shimamura T, Yasunaga J, et al. Integrated molecular analysis of adult T cell leukemia\/lymphoma. Nat Genet. 2015;47:1304\u201315.","journal-title":"Nat Genet"},{"key":"2725_CR8","doi-asserted-by":"publisher","first-page":"1686","DOI":"10.3389\/fmicb.2018.01686","volume":"9","author":"M Yamagishi","year":"2018","unstructured":"Yamagishi M, Fujikawa D, Watanabe T, Uchimaru K. HTLV-1-mediated epigenetic pathway to adult T-cell leukemia-lymphoma. Front Microbiol. 2018;9:1686.","journal-title":"Front Microbiol"},{"key":"2725_CR9","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.1182\/blood-2016-09-692574","volume":"129","author":"T Watanabe","year":"2017","unstructured":"Watanabe T. Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1\u2013infected T cells. Blood. 2017;129:1071\u201381.","journal-title":"Blood"},{"key":"2725_CR10","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1111\/cas.16388","volume":"116","author":"J Mizuike","year":"2025","unstructured":"Mizuike J, Suzuki K, Tosaka S, Kuze Y, Kobayashi S, Nakashima M, et al. Rewired chromatin structure and epigenetic gene dysregulation during HTLV-1 infection to leukemogenesis. Cancer Sci. 2025;116:513\u201323.","journal-title":"Cancer Sci"},{"key":"2725_CR11","doi-asserted-by":"publisher","first-page":"e517","DOI":"10.1016\/S1470-2045(14)70202-5","volume":"15","author":"K Ishitsuka","year":"2014","unstructured":"Ishitsuka K, Tamura K. Human T-cell leukaemia virus type I and adult T-cell leukaemia-lymphoma. Lancet Oncol. 2014;15:e517\u201326.","journal-title":"Lancet Oncol"},{"key":"2725_CR12","doi-asserted-by":"publisher","first-page":"1062","DOI":"10.3389\/fmicb.2020.01062","volume":"11","author":"H El Hajj","year":"2020","unstructured":"El Hajj H, Tsukasaki K, Cheminant M, Bazarbachi A, Watanabe T, Hermine O. Novel treatments of adult T Cell leukemia lymphoma. Front Microbiol. 2020;11:1062.","journal-title":"Front Microbiol"},{"key":"2725_CR13","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1200\/JCO.2011.37.3472","volume":"30","author":"T Ishida","year":"2012","unstructured":"Ishida T, Joh T, Uike N, Yamamoto K, Utsunomiya A, Yoshida S, et al. Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-Cell leukemia-lymphoma: a multicenter phase II study. J Clin Oncol. 2012;30:837\u201342.","journal-title":"J Clin Oncol"},{"key":"2725_CR14","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/S0140-6736(18)32984-2","volume":"393","author":"S Horwitz","year":"2019","unstructured":"Horwitz S, O\u2019Connor OA, Pro B, Illidge T, Fanale M, Advani R, et al. Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet. 2019;393:229\u201340.","journal-title":"Lancet"},{"key":"2725_CR15","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1038\/s41586-024-07103-x","volume":"627","author":"M Yamagishi","year":"2024","unstructured":"Yamagishi M, Kuze Y, Kobayashi S, Nakashima M, Morishima S, Kawamata T, et al. Mechanisms of action and resistance in histone methylation-targeted therapy. Nature. 2024;627:221\u20138.","journal-title":"Nature"},{"key":"2725_CR16","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1111\/j.1365-2141.2004.04999.x","volume":"126","author":"K Karube","year":"2004","unstructured":"Karube K, Ohshima K, Tsuchiya T, Yamaguchi T, Kawano R, Suzumiya J, et al. Expression of FoxP3, a key molecule in CD4+CD25+ regulatory T cells, in adult T-cell leukaemia\/lymphoma cells. Br J Haematol. 2004;126:81\u20134.","journal-title":"Br J Haematol"},{"key":"2725_CR17","doi-asserted-by":"publisher","first-page":"2375","DOI":"10.1002\/ijc.24664","volume":"125","author":"F Toulza","year":"2009","unstructured":"Toulza F, Nosaka K, Takiguchi M, Pagliuca T, Mitsuya H, Tanaka Y, et al. FoxP3+ regulatory T cells are distinct from leukemia cells in HTLV-1\u2013associated adult T-cell leukemia. Int J Cancer. 2009;125:2375\u201382.","journal-title":"Int J Cancer"},{"key":"2725_CR18","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1172\/JCI111992","volume":"76","author":"T Uchiyama","year":"1985","unstructured":"Uchiyama T, Hori T, Tsudo M, Wano Y, Umadome H, Tamori S, et al. Interleukin-2 receptor (Tac antigen) expressed on adult T cell leukemia cells. J Clin Invest. 1985;76:446\u201353.","journal-title":"J Clin Invest"},{"key":"2725_CR19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1001274","volume":"7","author":"Y Satou","year":"2011","unstructured":"Satou Y, Yasunaga J, Zhao T, Yoshida M, Miyazato P, Takai K, et al. HTLV-1 bZIP factor induces T-cell lymphoma and systemic inflammation in vivo. PLoS Pathog. 2011;7:e1001274.","journal-title":"PLoS Pathog"},{"key":"2725_CR20","doi-asserted-by":"publisher","first-page":"1865","DOI":"10.1182\/blood-2010-12-326199","volume":"118","author":"T Zhao","year":"2011","unstructured":"Zhao T, Satou Y, Sugata K, Miyazato P, Green PL, Imamura T, et al. HTLV-1 bZIP factor enhances TGF-\u03b2 signaling through p300 coactivator. Blood. 2011;118:1865\u201376.","journal-title":"Blood"},{"key":"2725_CR21","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1158\/2643-3230.BCD-21-0044","volume":"2","author":"J Koya","year":"2021","unstructured":"Koya J, Saito Y, Kameda T, Kogure Y, Yuasa M, Nagasaki J, et al. Single-cell analysis of the multicellular ecosystem in viral carcinogenesis by HTLV-1. Blood Cancer Discov. 2021;2:450\u201367.","journal-title":"Blood Cancer Discov"},{"key":"2725_CR22","doi-asserted-by":"publisher","DOI":"10.1172\/JCI150472","volume":"131","author":"BJY Tan","year":"2021","unstructured":"Tan BJY, Sugata K, Reda O, Matsuo M, Uchiyama K, Miyazato P, et al. HTLV-1 infection promotes excessive T cell activation and transformation into adult T cell leukemia\/lymphoma. J Clin Invest. 2021;131:e150472.","journal-title":"J Clin Invest"},{"key":"2725_CR23","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1093\/intimm\/dxh366","volume":"18","author":"S Chen","year":"2006","unstructured":"Chen S, Ishii N, Ine S, Ikeda S, Fujimura T, Ndhlovu LC, et al. Regulatory T cell-like activity of Foxp3+ adult T cell leukemia cells. Int Immunol. 2006;18:269\u201377.","journal-title":"Int Immunol"},{"key":"2725_CR24","doi-asserted-by":"publisher","DOI":"10.1093\/discim\/kyae006","volume":"3","author":"M Ono","year":"2024","unstructured":"Ono M, Satou Y. Spectrum of Treg and self-reactive T cells: single cell perspectives from old friend HTLV-1. Discov Immunol. 2024;3:kyae006.","journal-title":"Discov Immunol"},{"key":"2725_CR25","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1111\/j.1365-2141.1991.tb08051.x","volume":"79","author":"M Shimoyama","year":"1991","unstructured":"Shimoyama M. Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. a report from the Lymphoma Study Group (1984-87). Br J Haematol. 1991;79:428\u201337.","journal-title":"Br J Haematol"},{"key":"2725_CR26","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25101-9","volume":"12","author":"M Yamagishi","year":"2021","unstructured":"Yamagishi M, Kubokawa M, Kuze Y, Suzuki A, Yokomizo A, Kobayashi S, et al. Chronological genome and single-cell transcriptome integration characterizes the evolutionary process of adult T cell leukemia-lymphoma. Nat Commun. 2021;12:4821.","journal-title":"Nat Commun"},{"key":"2725_CR27","doi-asserted-by":"publisher","first-page":"2851","DOI":"10.1158\/1078-0432.CCR-13-3169","volume":"20","author":"S Kobayashi","year":"2014","unstructured":"Kobayashi S, Nakano K, Watanabe E, Ishigaki T, Ohno N, Yuji K, et al. CADM1 expression and stepwise downregulation of CD7 are closely associated with clonal expansion of HTLV-I-infected cells in adult T-cell leukemia\/lymphoma. Clin Cancer Res. 2014;20:2851\u201361.","journal-title":"Clin Cancer Res"},{"key":"2725_CR28","doi-asserted-by":"publisher","first-page":"1211","DOI":"10.1182\/blood-2009-12-257410","volume":"116","author":"M Iwanaga","year":"2010","unstructured":"Iwanaga M, Watanabe T, Utsunomiya A, Okayama A, Uchimaru K, Koh K-R, et al. Human T-cell leukemia virus type I (HTLV-1) proviral load and disease progression in asymptomatic HTLV-1 carriers: a nationwide prospective study in Japan. Blood. 2010;116:1211\u20139.","journal-title":"Blood"},{"key":"2725_CR29","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1016\/j.ccell.2018.06.014","volume":"34","author":"M Nakagawa","year":"2018","unstructured":"Nakagawa M, Shaffer AL, Ceribelli M, Zhang M, Wright G, Huang DW, et al. Targeting the HTLV-I-regulated BATF3\/IRF4 transcriptional network in adult T cell leukemia\/lymphoma. Cancer Cell. 2018;34:286\u201397.e10.","journal-title":"Cancer Cell"},{"key":"2725_CR30","doi-asserted-by":"publisher","first-page":"13740","DOI":"10.1073\/pnas.1922884117","volume":"117","author":"Y Higuchi","year":"2020","unstructured":"Higuchi Y, Yasunaga J, Mitagami Y, Tsukamoto H, Nakashima K, Ohshima K, et al. HTLV-1 induces T cell malignancy and inflammation by viral antisense factor-mediated modulation of the cytokine signaling. Proc Natl Acad Sci USA. 2020;117:13740\u20139.","journal-title":"Proc Natl Acad Sci USA"},{"key":"2725_CR31","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/j.bbagrm.2015.11.003","volume":"1859","author":"S Haupt","year":"2016","unstructured":"Haupt S, S\u00f6ntgerath VSA, Leipe J, Schulze-Koops H, Skapenko A. Methylation of an intragenic alternative promoter regulates transcription of GARP. Biochim Biophys Acta. 2016;1859:223\u201334.","journal-title":"Biochim Biophys Acta"},{"key":"2725_CR32","doi-asserted-by":"publisher","first-page":"587","DOI":"10.3390\/v14030587","volume":"14","author":"M Yamagishi","year":"2022","unstructured":"Yamagishi M, Suzuki Y, Watanabe T, Uchimaru K. Clonal selection and evolution of HTLV-1-infected cells driven by genetic and epigenetic alteration. Viruses. 2022;14:587.","journal-title":"Viruses"},{"key":"2725_CR33","doi-asserted-by":"publisher","first-page":"2321","DOI":"10.1016\/j.celrep.2019.10.083","volume":"29","author":"M Yamagishi","year":"2019","unstructured":"Yamagishi M, Hori M, Fujikawa D, Ohsugi T, Honma D, Adachi N, et al. Targeting excessive EZH1 and EZH2 activities for abnormal histone methylation and transcription network in malignant lymphomas. Cell Rep. 2019;29:2321\u201337.e7.","journal-title":"Cell Rep"},{"key":"2725_CR34","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.ccr.2011.12.015","volume":"21","author":"M Yamagishi","year":"2012","unstructured":"Yamagishi M, Nakano K, Miyake A, Yamochi T, Kagami Y, Tsutsumi A, et al. Polycomb-mediated loss of miR-31 activates NIK-dependent NF-\u03baB pathway in adult T Cell leukemia and other cancers. Cancer Cell. 2012;21:121\u201335.","journal-title":"Cancer Cell"},{"key":"2725_CR35","doi-asserted-by":"publisher","first-page":"1790","DOI":"10.1182\/blood-2015-08-662593","volume":"127","author":"D Fujikawa","year":"2016","unstructured":"Fujikawa D, Nakagawa S, Hori M, Kurokawa N, Soejima A, Nakano K, et al. Polycomb-dependent epigenetic landscape in adult T-cell leukemia. Blood. 2016;127:1790\u2013802.","journal-title":"Blood"},{"key":"2725_CR36","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1182\/blood.2022016862","volume":"141","author":"K Izutsu","year":"2023","unstructured":"Izutsu K, Makita S, Nosaka K, Yoshimitsu M, Utsunomiya A, Kusumoto S, et al. An open-label, single-arm phase 2 trial of valemetostat for relapsed or refractory adult T-cell leukemia\/lymphoma. Blood. 2023;141:1159\u201368.","journal-title":"Blood"},{"key":"2725_CR37","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1038\/s41423-023-01036-7","volume":"20","author":"J Wang","year":"2023","unstructured":"Wang J, Zhao X, Wan YY. Intricacies of TGF-\u03b2 signaling in Treg and Th17 cell biology. Cell Mol Immunol. 2023;20:1002\u201322.","journal-title":"Cell Mol Immunol"},{"key":"2725_CR38","doi-asserted-by":"publisher","first-page":"1677","DOI":"10.1038\/s41423-021-00701-z","volume":"18","author":"P Lehmkuhl","year":"2021","unstructured":"Lehmkuhl P, Gentz M, Garcia de Otezya AC, Grimbacher B, Schulze-Koops H, Skapenko A. Dysregulated immunity in PID patients with low GARP expression on Tregs due to mutations in LRRC32. Cell Mol Immunol. 2021;18:1677\u201391.","journal-title":"Cell Mol Immunol"},{"key":"2725_CR39","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1084\/jem.20042276","volume":"201","author":"JC Marie","year":"2005","unstructured":"Marie JC, Letterio JJ, Gavin M, Rudensky AY. TGF-\u03b21 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J Exp Med. 2005;201:1061\u20137.","journal-title":"J Exp Med"},{"key":"2725_CR40","doi-asserted-by":"publisher","first-page":"6200","DOI":"10.1016\/j.cell.2024.08.036","volume":"187","author":"M Jin","year":"2024","unstructured":"Jin M, Seed RI, Cai G, Shing T, Wang L, Ito S, et al. Dynamic allostery drives autocrine and paracrine TGF-\u03b2 signaling. Cell. 2024;187:6200\u201319.e23.","journal-title":"Cell"},{"key":"2725_CR41","doi-asserted-by":"publisher","first-page":"2137","DOI":"10.1182\/blood.V97.7.2137","volume":"97","author":"N Mori","year":"2001","unstructured":"Mori N, Morishita M, Tsukazaki T, Giam C-Z, Kumatori A, Tanaka Y, et al. Human T-cell leukemia virus type I oncoprotein Tax represses Smad-dependent transforming growth factor \u03b2 signaling through interaction with CREB-binding protein\/p300. Blood. 2001;97:2137\u201344.","journal-title":"Blood"},{"key":"2725_CR42","doi-asserted-by":"publisher","first-page":"4157","DOI":"10.1038\/onc.2010.172","volume":"29","author":"S Nakahata","year":"2010","unstructured":"Nakahata S, Yamazaki S, Nakauchi H, Morishita K. Downregulation of ZEB1 and overexpression of Smad7 contribute to resistance to TGF-\u03b21-mediated growth suppression in adult T-cell leukemia\/lymphoma. Oncogene. 2010;29:4157\u201369.","journal-title":"Oncogene"},{"key":"2725_CR43","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2309925121","volume":"121","author":"T Shichijo","year":"2024","unstructured":"Shichijo T, Yasunaga J, Sato K, Nosaka K, Toyoda K, Watanabe M, et al. Vulnerability to APOBEC3G linked to the pathogenicity of deltaretroviruses. Proc Natl Acad Sci USA. 2024;121:e2309925121.","journal-title":"Proc Natl Acad Sci USA"},{"key":"2725_CR44","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.928450","volume":"13","author":"N Zimmer","year":"2022","unstructured":"Zimmer N, Trzeciak ER, Graefen B, Satoh K, Tuettenberg A. GARP as a therapeutic target for the modulation of regulatory T cells in cancer and autoimmunity. Front Immunol. 2022;13:928450.","journal-title":"Front Immunol"},{"key":"2725_CR45","doi-asserted-by":"publisher","first-page":"5057","DOI":"10.4049\/jimmunol.1300065","volume":"190","author":"AX Zhou","year":"2013","unstructured":"Zhou AX, Kozhaya L, Fujii H, Unutmaz D. GARP\u2013TGF-\u03b2 complexes negatively regulate regulatory T cell development and maintenance of peripheral CD4+ T cells in vivo. J Immunol. 2013;190:5057\u201364.","journal-title":"J Immunol"},{"key":"2725_CR46","doi-asserted-by":"publisher","first-page":"20105","DOI":"10.1074\/jbc.M115.655340","volume":"290","author":"C Huygens","year":"2015","unstructured":"Huygens C, Li\u00e9nart S, Dedobbeleer O, Stockis J, Gauthy E, Coulie PG, et al. Lysosomal-associated transmembrane protein 4B (LAPTM4B) decreases transforming growth factor \u03b21 (TGF-\u03b21) production in human regulatory T cells. J Biol Chem. 2015;290:20105\u201316.","journal-title":"J Biol Chem"},{"key":"2725_CR47","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1093\/intimm\/dxab027","volume":"33","author":"K Satoh","year":"2021","unstructured":"Satoh K, Kobayashi Y, Fujimaki K, Hayashi S, Ishida S, Sugiyama D, et al. Novel anti-GARP antibody DS-1055a augments anti-tumor immunity by depleting highly suppressive GARP+ regulatory T cells. Int Immunol. 2021;33:435\u201346.","journal-title":"Int Immunol"},{"key":"2725_CR48","doi-asserted-by":"publisher","first-page":"284ra56","DOI":"10.1126\/scitranslmed.aaa1983","volume":"7","author":"J Cuende","year":"2015","unstructured":"Cuende J, Li\u00e9nart S, Dedobbeleer O, van der Woning B, De Boeck G, Stockis J, et al. Monoclonal antibodies against GARP\/TGF-\u03b21 complexes inhibit the immunosuppressive activity of human regulatory T cells in vivo. Sci Transl Med. 2015;7:284ra56.","journal-title":"Sci Transl Med"},{"key":"2725_CR49","doi-asserted-by":"publisher","first-page":"1520","DOI":"10.1158\/1078-0432.CCR-09-2697","volume":"16","author":"T Ishii","year":"2010","unstructured":"Ishii T, Ishida T, Utsunomiya A, Inagaki A, Yano H, Komatsu H, et al. Defucosylated humanized anti-CCR4 monoclonal antibody KW-0761 as a novel immunotherapeutic agent for adult T-cell leukemia\/lymphoma. Clin Cancer Res. 2010;16:1520\u201331.","journal-title":"Clin Cancer Res"},{"key":"2725_CR50","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27574-0","volume":"12","author":"Y Maeda","year":"2021","unstructured":"Maeda Y, Wada H, Sugiyama D, Saito T, Irie T, Itahashi K, et al. Depletion of central memory CD8+ T cells might impede the antitumor therapeutic effect of Mogamulizumab. Nat Commun. 2021;12:7280.","journal-title":"Nat Commun"}],"container-title":["Leukemia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02725-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02725-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02725-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T09:03:06Z","timestamp":1758790986000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02725-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,4]]},"references-count":50,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,10]]}},"alternative-id":["2725"],"URL":"https:\/\/doi.org\/10.1038\/s41375-025-02725-0","relation":{},"ISSN":["0887-6924","1476-5551"],"issn-type":[{"value":"0887-6924","type":"print"},{"value":"1476-5551","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,4]]},"assertion":[{"value":"30 January 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 July 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 July 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 August 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"S.Kozuma and MH are employees of Daiichi Sankyo Co., Ltd. Daiichi Sankyo holds patents on DS-1055a. All other authors have no competing interests to declare.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All methods described in this manuscript were performed in accordance with the relevant guidelines and regulations. The study has been approved by the Institutional Review Board of the University of Tokyo (No. 23-482). Written informed consents were obtained from all patients. This study does not include any identifiable images from human participants.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}]}}