Azidothymidine potentiates the immunomodulatory function of interferon-α in adult T cell leukemia/lymphoma

Adult T cell leukemia/lymphoma (ATLL), caused by human T cell leukemia virus type 1, is an aggressive malignancy with limited treatment options. Although the combination therapy of azidothymidine (AZT) and interferon-α (IFN-α) has demonstrated clinical efficacy in ATLL, its underlying mechanism remains unclear. In this study, through comprehensive analyses, we reveal that the combination therapy can enhance CD8+ T cell function both in vitro and in vivo: it promotes cytotoxic T lymphocyte (CTL)-mediated killing of ATLL cell lines, and exhibits antitumor activities in immunocompetent but not immunodeficient mouse xenograft models (MC38 and EL4 were used due to the lack of immunocompetent mouse model for ATLL). Granzyme B, which is downregulated in ATLL patients, was found to be key to the effectiveness of AZT/IFN-α therapy. In addition, AZT promotes IFN-α-mediated antigen processing and presentation, and it further transcriptionally upregulates the expression of the ATLL antigen HBZ. Collectively, AZT could potentiate the immunomodulatory function of IFN-α in ATLL likely via enhancing tumor antigen expression and processing and boosting CTL activities. This study suggests a key role of immunostimulation in AZT/IFN-α-treated ATLL and may provide mechanistic insights into the development of novel therapies.