Cytarabine-induced TNFα promotes the expansion and suppressive functions of myeloid-derived suppressor cells in acute myeloid leukaemia

Acute myeloid leukaemia (AML) is very common haematopoietic malignancies with poor prognosis. Chemotherapy is still a mainstay therapy for AML patients. AML microenvironment plays critical roles in therapy response. However, the role of chemotherapy in AML microenvironment is poorly understood. In this study, we report that cytarabine (AraC)-triggered TNF alpha from AMT, cells expanded myeloid-derived suppressor cells (MDSCs) and enhanced MDSC functions and survival through activating IL-6/STAT3 and NF kappa B pathways. Blockade of TNF alpha in conditioned medium-derived AraC-treated AML cells (AraC_CM) impaired MDSC expansion and functions, reduced IL-6 secretion and the level of activated STAT3. Inhibiting IL6 or STAT3 abrogated AraC_CM-mediated MDSC suppressive function. Additionally, inhibiting TNF alpha also impaired AraC_CM-mediated NF kappa B activation. Blocking NF kappa B activation reduced MDSC viability induced by AraC_CM. Together, these results provided a role of AraC-induced TNF alpha in MDSC expansion and functions and suggest that targeting TNF alpha may benefit AML patients to current anticancer strategies by blocking MDSC-mediated immunosuppression.