Loss of interleukin-10 activates innate immunity to eradicate adult T-cell leukemia-initiating cells
Hiba El Hajj,
Rita Hleihel,
Marwan El Sabban,
Julie Bruneau,
Ghazi Zaatari,
Morgane Cheminant,
Ambroise Marçais,
Abdou Akkouche,
Hideki Hasegawa,
William Hall,
Hugues De Thé,
Olivier Hermine,
Ali Bazarbachi
Affiliations
Hiba El Hajj
Department of Internal Medicine, Faculty of Medicine, American University of Beirut, 1107 2020 Beirut, Lebanon; Department of Experimental Pathology, Microbiology and Immunology, Faculty of Medicine, American University of Beirut, 1107 2020 Beirut
Rita Hleihel
Department of Internal Medicine, Faculty of Medicine, American University of Beirut, 1107 2020 Beirut
Marwan El Sabban
Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, 1107 2020 Beirut
Julie Bruneau
Institut Imagine - INSERM U1163, Necker Hospital, University of Paris, 75015 Paris France; Department of Pathology, Necker Hospital, University of Paris, Assistance Publique Hôpitaux de Paris, 75015 Paris
Ghazi Zaatari
Department of Pathology and Laboratory Medicine, Faculty of Medicine, American University of Beirut, 1107 2020 Beirut
Morgane Cheminant
Institut Imagine - INSERM U1163, Necker Hospital, University of Paris, 75015 Paris France; Department of Hematology, Necker Hospital, University of Paris, Assistance Publique Hôpitaux de Paris, 75015 Paris
Ambroise Marçais
Department of Hematology, Necker Hospital, University of Paris, Assistance Publique Hôpitaux de Paris, 75015 Paris, France; INSERM UMR 1151, University of Paris, Paris
Abdou Akkouche
Department of Internal Medicine, Faculty of Medicine, American University of Beirut, 1107 2020 Beirut
Hideki Hasegawa
National Institute of Infectious Diseases, 208-0011 Tokyo
William Hall
University College Dublin, 47335 Dublin, Ireland; GI CoRE, Center for Zoonosis Control, Hokkaido University, Sapporo
Hugues De Thé
INSERM UMR 944, Equipe labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d’Hématologie, Hôpital St. Louis 1, Avenue Claude Vellefaux 75475 PARIS cedex 10 France; CNRS UMR 7212, Hôpital St. Louis 1, Avenue Claude Vellefaux 75475 PARIS cedex 10 France; College de France, Place Marcelin Berthelot 75005 PARIS France
Olivier Hermine
Institut Imagine - INSERM U1163, Necker Hospital, University of Paris, 75015 Paris France; Department of Hematology, Necker Hospital, University of Paris, Assistance Publique Hôpitaux de Paris, 75015 Paris
Ali Bazarbachi
Department of Internal Medicine, Faculty of Medicine, American University of Beirut, 1107 2020 Beirut, Lebanon; Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, 1107 2020 Beirut
Adult T cell leukemia/lymphoma (ATL) is associated to chronic human T cell leukemia virus type 1 (HTLV-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 Taxdriven 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 (LIC) eradication and provide a strong rational to test AS/IFNα/anti-IL10 combination in ATL.
