新たな抗体療法で難治性血液がんを制圧へ～がん細胞の除去と免疫活性化の二重効果～

2025-08-07 東京大学

ATL細胞におけるGARP-TGF-β経路と抗GARP抗体

<関連情報>

• https://www.k.u-tokyo.ac.jp/information/category/press/11706.html
• https://www.k.u-tokyo.ac.jp/information/upload/17b3f3ee75c35e41bec6ea6178f7c43c2a5e43f4.pdf
• https://www.nature.com/articles/s41375-025-02725-0

成人T細胞白血病/リンパ腫におけるGARP–TGF-β軸を標的とした双方向の抗腫瘍および免疫学的戦略 Bidirectional anti-tumor and immunological strategies by targeting GARP–TGF-β axis in adult T-cell leukemia/lymphoma

Kako Suzuki,Seina Kusayanagi,Yuta Kuze,Masato Hata,Shiho Kozuma,Koji Jimbo,Yasuhito Nannya,Yutaka Suzuki,Kaoru Uchimaru & Makoto Yamagishi
Leukemia  Published:04 August 2025
DOI:https://doi.org/10.1038/s41375-025-02725-0

Abstract

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-β (TGF-β). The GARP–TGF-β 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.