Medical Laboratory Center, The Third Affiliated Hospital of Guizhou Medical University, Guiyang, China.
Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, School of Basic Medical Science, Guizhou Medical University, Guiyang, China.
Scand J Immunol. 2022 Jun;95(6):e13158. doi: 10.1111/sji.13158. Epub 2022 Mar 20.
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 TNFα from AML cells expanded myeloid-derived suppressor cells (MDSCs) and enhanced MDSC functions and survival through activating IL-6/STAT3 and NFκB pathways. Blockade of TNFα 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 TNFα also impaired AraC_CM-mediated NFκB activation. Blocking NFκB activation reduced MDSC viability induced by AraC_CM. Together, these results provided a role of AraC-induced TNFα in MDSC expansion and functions and suggest that targeting TNFα may benefit AML patients to current anticancer strategies by blocking MDSC-mediated immunosuppression.
急性髓系白血病（AML）是一种非常常见的造血系统恶性肿瘤，预后较差。化疗仍然是 AML 患者的主要治疗方法。AML 微环境在治疗反应中起着关键作用。然而，化疗在 AML 微环境中的作用尚未被充分了解。在这项研究中，我们报告了阿糖胞苷（AraC）触发 AML 细胞产生的 TNFα 通过激活 IL-6/STAT3 和 NFκB 通路，扩增髓系来源的抑制细胞（MDSCs）并增强 MDSC 的功能和存活。阻断条件培养基中 AraC 处理的 AML 细胞（AraC_CM）中产生的 TNFα 会损害 MDSC 的扩增和功能，减少 IL-6 的分泌和激活的 STAT3 水平。抑制 IL6 或 STAT3 会阻断 AraC_CM 介导的 MDSC 抑制功能。此外，抑制 TNFα 还会损害 AraC_CM 介导的 NFκB 激活。阻断 NFκB 激活可降低 AraC_CM 诱导的 MDSC 活力。总之，这些结果表明 AraC 诱导的 TNFα 在 MDSC 的扩增和功能中起作用，并提示靶向 TNFα 可能通过阻断 MDSC 介导的免疫抑制作用，有益于 AML 患者的现有抗癌策略。
