The combination of arsenic, interferon-alpha, and zidovudine restores an immunocompetent-like cytokine expression profile in patients with adult T-cell leukemia lymphoma

Background: HTLV-I associated adult T-cell leukemia/lymphoma (ATL) carries a dismal prognosis due to chemo-resistance and immuno-compromised micro-environment. The combination of zidovudine and interferon-alpha (IFN) significantly improved survival in ATL. Promising results were reported by adding arsenic trioxide to zidovudine and IFN. Results: Here we assessed Th1/Th2/T-reg cytokine gene expression profiles in 16 ATL patients before and 30 days after treatment with arsenic/IFN/zidovudine, in comparison with HTLV-I healthy carriers and sero-negative blood donors. ATL patients at diagnosis displayed a T-reg/Th2 cytokine profile with significantly elevated transcript levels of Foxp3, interleukin-10 (IL-10), and IL-4 and had a reduced Th1 profile evidenced by decreased transcript levels of interferon-gamma (IFN-gamma) and IL-2. Most patients (15/16) responded, with CD4(+)CD25(+) cells significantly decreasing after therapy, paralleled by decreases in Foxp3 transcript. Importantly, arsenic/IFN/zidovudine therapy sharply diminished IL-10 transcript and serum levels concomittant with decrease in IL-4 and increases in IFN-gamma and IL-2 mRNA, whether or not values were adjusted to the percentage of CD4(+)CD25(+) cells. Finally, IL-10 transcript level negatively correlated with clinical response at Day 30. Conclusions: The observed shift from a T-reg/Th2 phenotype before treatment toward a Th1 phenotype after treatment with arsenic/IFN/zidovudine may play an important role in restoring an immuno-competent micro-environment, which enhances the eradication of ATL cells and the prevention of opportunistic infections.