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T-cell Leukemia
Loss of interleukin-10 activates innate immunity to eradicate adult T-cell leukemia-initiating cells
Ferrata Storti Foundation
Haematologica 2021 Volume 106(5):1443-1456
Hiba El Hajj,1 Rita Hleihel,2,3 Marwan El Sabban,3 Julie Bruneau,4,5
Ghazi Zaatari,6 Morgane Cheminant,4,7 Ambroise Marçais,7,8
Abdou Akkouche,1 Hideki Hasegawa,9 William Hall,10,11 Hugues De Thé,12-14 Olivier Hermine4,7 and Ali Bazarbachi2,3
1Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon; 2Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut, Lebanon; 3Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon; 4Institut Imagine - INSERM U1163, Necker Hospital, University of Paris, Paris, France; 5Department of Pathology, Necker Hospital, University of Paris, Assistance Publique Hôpitaux de Paris, Paris, France; 6Department of Pathology and Laboratory Medicine, Faculty of Medicine, American University of Beirut, Beirut, Lebanon; 7Department of Hematology, Necker Hospital, University of Paris, Assistance Publique Hôpitaux de Paris, Paris, France; 8INSERM UMR 1151, University of Paris, Paris, France; 9National Institute of Infectious Diseases, Tokyo, Japan; 10University College Dublin, Dublin, Ireland; 11GI CoRE, Center for Zoonosis Control, Hokkaido University, Sapporo, Japan; 12INSERM UMR 944, Equipe Labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d’Hématologie, Hôpital St. Louis, Paris, France; 13CNRS UMR 7212, Hôpital St. Louis, Paris, Paris France and 14College de France, Paris, France
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 microenvi- ronment, followed by innate immunity-mediated clearance of Tax-driven leukemic cells. Accordingly, anti-IL-10 monoclonal antibodies significant- ly 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.
Introduction
Adult T-cell leukemia/lymphoma (ATL) is a rare hematologic malignancy with a dismal prognosis1 and is initiated by the human T-cell leukemia virus type 1 (HTLV- 1).2 ATL develops after an extended latency period and is preceded by oligoclonal expansion of activated HTLV-1-infected T cells,3 as a result of initial expression of the viral transactivator Tax. Tax modulates several cellular pathways4-7 and is a powerful oncogene; transgenic expression of Tax alone in mice induces murine ATL.8 Although Tax protein expression is very low in most patients with ATL, long-term survival of the bulk of ATL cells may depend on transient bursts of Tax expression in some, if not the majority, of ATL cells and/or in HTLV-1-infected non- malignant cells.9-11 This renders Tax an attractive therapeutic target, which has been further asserted by the efficacy of a Tax peptide-pulsed dendritic cell vaccine in treating patients with Tax-positive ATL.12
Correspondence:
ALI BAZARBACHI
bazarbac@aub.edu.lb
OLIVIER HERMINE
ohermine@gmail.com
HIBA EL HAJJ
he21@aub.edu.lb
Received: June 24, 2020. Accepted: December 4, 2020. Pre-published: February 11, 2021.
https://doi.org/10.3324/haematol.2020.264523
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