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

Adult T-cell leukemia/lymphoma (ATL) is associated with chronic human T-cell leukemia virus type 1 infection and carries a poor pr o gnosi s. Arsenic tr ioxide (AS) and inter feron-alpha (IFN) together selectively trigger Tax viral oncoprotein degradation and cure Tax-driven murine ATL. AS/IFN/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/IFN-induced abrogation of leukemiainitiating 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/IFNtherapy. 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/IFN/anti-IL10 combination in ATL.