Loss of interleukin-10 activates innate immunity to eradicate adult T-cell leukemia-initiating cells
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Ferrata Storti Foundation
Abstract
Adult T-cell leukemia/lymphoma (ATL) is associated with chronic human T-cell leukemia virus type 1 infection and carries a poor prognosis. Arsenic trioxide (AS) and interferon-alpha (IFNα) together selectively trigger Tax viral oncoprotein degradation and cure Tax-driven murine ATL. AS/IFNα/zidovudine treatment achieves a high response rate in patients with chronic ATL. Interleukin 10 (IL-10) is an immuno-suppressive cytokine whose expression is activated by Tax. Here we show that, in ATL, AS/IFNα-induced abrogation of leukemia-initiating cell activity requires IL-10 expression shutoff. Loss of IL-10 secretion drives production of inflammatory cytokines by the microenvironment, followed by innate immunity-mediated clearance of Tax-driven leukemic cells. Accordingly, anti-IL-10 monoclonal antibodies significantly increased the efficiency of AS/IFNα therapy. These results emphasize the sequential targeting of malignant ATL cells and their immune microenvironment in leukemia-initiating cell eradication and provide a strong rationale to test the AS/IFNα/anti-IL10 combination in ATL. © 2021 Ferrata Storti Foundation
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Adult, Animals, Human t-lymphotropic virus 1, Humans, Immunity, innate, Interferon-alpha, Interleukin-10, Leukemia-lymphoma, adult t-cell, Mice, Tumor microenvironment, Alpha interferon, Alpha2a interferon, Anti-interleukin 1o antibody, Antibody, Arsenic trioxide, Bortezomib, Clodronic acid, Immunoglobulin enhancer binding protein, Interleukin 10, Interleukin 10 antibody, Liposome, Monoclonal antibody, Recombinant alpha interferon, Recombinant interleukin 10, Tax protein, Unclassified drug, Zidovudine, Animal experiment, Animal model, Apoptosis assay, Article, Cd25+ t lymphocyte, Cell selection, Controlled study, Cytokine release, Enzyme linked immunosorbent assay, Flow cytometry, Histochemistry, Hypercalcemia, Immunoblotting, Innate immunity, Leukocytosis, Mouse, Nonhuman, Peripheral blood mononuclear cell, Protein expression, Real time polymerase chain reaction, Scid mouse, Splenomegaly, T cell leukemia, Animal, Genetics, Human