| RRC ID |
85402
|
| Author |
Suzuki K, Kusayanagi S, Kuze Y, Hata M, Kozuma S, Jimbo K, Nannya Y, Suzuki Y, Uchimaru K, Yamagishi M.
|
| Title |
Bidirectional anti-tumor and immunological strategies by targeting GARP-TGF-β axis in adult T-cell leukemia/lymphoma.
|
| Journal |
Leukemia
|
| 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.
|
| Published |
2025-8-4
|
| DOI |
10.1038/s41375-025-02725-0
|
| PII |
10.1038/s41375-025-02725-0
|
| PMID |
40759773
|
| PMC |
PMC12463658
|
| MeSH |
Animals
Antibodies, Monoclonal / pharmacology
Cell Proliferation
Humans
Leukemia-Lymphoma, Adult T-Cell* / drug therapy
Leukemia-Lymphoma, Adult T-Cell* / immunology
Leukemia-Lymphoma, Adult T-Cell* / metabolism
Leukemia-Lymphoma, Adult T-Cell* / pathology
Membrane Proteins* / antagonists & inhibitors
Membrane Proteins* / genetics
Membrane Proteins* / immunology
Membrane Proteins* / metabolism
Mice
Signal Transduction / drug effects
T-Lymphocytes, Regulatory / immunology
Transforming Growth Factor beta* / metabolism
|
| IF |
8.665
|
| Resource |
| Human and Animal Cells |
ATN-1(RCB1440)
Jurkat(RCB3052)
CCRF-CEM(RCB1980) |
| DNA material |
CS-RfA-EVBsd (RDB06090)
pENTR4-H1 (RDB04395)
pCMV-VSV-G-RSV-Rev (RDB04393)
pCAG-HIVgp (RDB04394) |
