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Blood Cancer J., Feb 10 2025, | https://doi.org/10.1158/2643-3230.BCD-24-0140
SOCS1 protects acute myeloid leukemia against allogeneic T cell-mediated cytotoxicity
Enoch Tin 1,2, Sergio Rutella 3, Ismat Khatri 1, Yoosu Na 1, Yongran Yan 4, Neil MacLean 4, Jayakumar Vadakekolathu 3, Mark D. Minden 4, Aaron D. Schimmer 4*, JongBok Lee 1,5*, Li Zhang 1,2,6*
1Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.
2Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
3John van Geest Cancer Research Center, School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom.
4Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
5Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
6Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
*Corresponding Author : Dr. Li Zhang, Dr. JongBok Lee, Dr. Aaron D. Schimmer
1Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.
2Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
3John van Geest Cancer Research Center, School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom.
4Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
5Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
6Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
*Corresponding Author : Dr. Li Zhang, Dr. JongBok Lee, Dr. Aaron D. Schimmer
Abstract
Despite the curative potential of allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia (AML), its efficacy is limited by intrinsic resistance of cancer cells to donor-derived T-cell cytotoxicity. Using a genome-wide CRISPR screen, we identified the SOCS1-JAK1-STAT1 pathway as a mediator of AML susceptibility to T cells. SOCS1 knockdown in AML cells sensitized them to killing by allogeneic T cells, whereas SOCS1 overexpression in AML cells induced resistance to T-cell anti-leukemic activity. Mechanistically, SOCS1 protected AML cells from T-cell killing by antagonizing IFNγ-JAK1-induced ICAM-1 expression. Furthermore, primary AML cells with lower SOCS1 expression correlated with better overall survival in patients, especially those with a lower exhausted CD8+ T-cell score. Thus, this study reveals SOCS1 and its downstream mediators as a potential targetable pathway to enhance T cell-based immunotherapy for AML.
논문정보
- Research article
- 2025년 02월 (BRIC 등록일 2025-02-14)
- 국외 연구진
- 의약학 > 면역의학
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