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

Haematologica. 2021 May 1;106(5):1443-1456. doi: 10.3324/haematol.2020.264523.

Abstract

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.

Grant support

FundingThis work was supported by the American University of Beirut Medical Practice Plan, the University Research Board, the Lebanese National Council for Scientific Research, the Lady TATA Memorial Trust; the European Research Council (Senior Grant 268729–STEMAPL) (to HdT), the Ligue Nationale Contre le Cancer, Centre National de la Recherche Scientifique, Association de Recherche Contre le Cancer, Institut National Contre le Cancer, and Cancerople Ile de France (to OH).