Loss of interleukin-10 activates innate immunity to eradicate adult T-cell leukemia-initiating cells

• Published in: Haematologica (Roma) 2021-05, Vol.106 (5), p.1443-1456
• Main Authors: El Hajj, Hiba, Hleihel, Rita, El Sabban, Marwan, Bruneau, Julie, Zaatari, Ghazi, Cheminant, Morgane, Marçais, Ambroise, Akkouche, Abdou, Hasegawa, Hideki, Hall, William, De Thé, Hugues, Hermine, Olivier, Bazarbachi, Ali
• Format: Article
• Language: English
• Subjects: Adult; Animals; Human T-lymphotropic virus 1; Humans; Immunity, Innate; Interferon-alpha; Interleukin-10 - genetics; Leukemia-Lymphoma, Adult T-Cell - drug therapy; Life Sciences; Mice; Tumor Microenvironment
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2020.264523

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.