1. Double-negative T cells utilize a TNFα-JAK1-ICAM-1 cytotoxic axis against acute myeloid leukemia.
- Author
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Tin E, Lee JB, Khatri I, Na Y, Minden MD, and Zhang L
- Subjects
- Humans, Cytotoxicity, Immunologic, Signal Transduction, Cell Line, Tumor, T-Lymphocyte Subsets metabolism, T-Lymphocyte Subsets immunology, Leukemia, Myeloid, Acute metabolism, Intercellular Adhesion Molecule-1 metabolism, Tumor Necrosis Factor-alpha metabolism, Janus Kinase 1 metabolism
- Abstract
Abstract: Allogeneic double-negative T cells (DNTs) are a rare T-cell subset that effectively target acute myeloid leukemia (AML) without inducing graft-versus-host disease in an allogeneic setting. A phase 1 clinical trial demonstrated the feasibility, safety, and potential efficacy of allogeneic DNT therapy among patients with relapsed AML. However, the molecular mechanisms of DNT-mediated cytotoxicity against AML remain elusive. Thus, we used a flow cytometry-based high throughput screening to compare the surface molecule expression profile on DNTs during their interaction with DNT-susceptible or -resistant AML cells and identified a tumor necrosis factor α (TNFα)-dependent cytotoxic pathway in DNT-AML interaction. TNFα secreted by DNTs, upon encountering susceptible AML targets, sensitized AML cells to DNT-mediated killing, including those otherwise resistant to DNTs. Mechanistically, TNFα upregulated ICAM-1 on AML cells through a noncanonical JAK1-dependent pathway. DNTs then engaged with AML cells more effectively through an ICAM-1 receptor, lymphocyte function-associated antigen 1, leading to enhanced killing. These results reveal a TNFα-JAK1-ICAM-1 axis in DNT-mediated cytotoxicity against AML to improve therapeutic efficacy., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2024
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