Lamprianidou Eleftheria, Kordella Chryssoula, Kazachenka Anastasiya, Zoulia Emmanouela, Bernard Elsa, Filia Anastasia, Laidou Stamatia, Garantziotis Panayiotis, Vassilakopoulos Theodoros P, Papageorgiou Sotirios G, Pappa Vassiliki, Galanopoulos Athanasios G, Viniou Nora, Nakou Evangelia, Kalafati Lydia, Chatzidimitriou Anastasia, Kassiotis George, Papaemmanuil Elli, Mitroulis Ioannis, Kotsianidis Ioannis
Department of Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece.
Retroviral Immunology, The Francis Crick Institute, London, United Kingdom.
Blood Adv. 2021 Jan 12;5(1):129-142. doi: 10.1182/bloodadvances.2020002351.
CD4+ T cells orchestrate immune responses and are actively engaged in shaping tumor immunity. Signal transducer and activator of transcription (STAT) signaling controls the epigenetic tuning of CD4+ T-cell differentiation and polarization, and perturbed STAT signaling networks in CD4+ T cells subvert antitumor immunity in malignancies. Azacitidine (AZA), the mainstay therapy for high-risk myelodysplastic syndromes (HR-MDS), affects CD4+ T-cell polarization and function, but whether this contributes to AZA efficacy is currently unknown. By using functional proteomic, transcriptomic, and mutational analyses in 73 HR-MDS patients undergoing AZA therapy, we demonstrate that responding patients exhibited a coordinated CD4+ T-cell immune response and downregulated the inflammatory cytokine signaling pathways in CD4+ T cells after AZA, in contrast to nonresponders who upregulated the same pathways. We further observed an AZA-mediated downregulation of intereukin-6 (IL-6)-induced STAT3 phosphorylation in CD4+FOXP3- conventional T cells (Tcons) that correlated independently with better response and survival, whereas it was also not associated with the mutation number and profile of the patients. The AZA-induced downregulation of IL-6/STAT3 axis in Tcons restored the STAT signaling architecture in CD4+ T-cell subsets, whereas STAT signaling networks remained disorganized in patients who upregulated IL-6/STAT3 activity in Tcons. Given the pivotal role of CD4+ T cells in adaptive immunity, our findings suggest that the downregulation of the IL-6/STAT3 pathway in Tcons potentially constitutes a previously unrecognized immune-mediated mechanism of action of AZA and sets the scene for developing rational strategies of AZA combinations with IL-6/STAT3 axis inhibitors.
CD4+ T细胞协调免疫反应，并积极参与塑造肿瘤免疫。信号转导和转录激活因子（STAT）信号传导控制CD4+ T细胞分化和极化的表观遗传调控，而CD4+ T细胞中STAT信号网络的紊乱会破坏恶性肿瘤中的抗肿瘤免疫。阿扎胞苷（AZA）是高危骨髓增生异常综合征（HR-MDS）的主要治疗方法，它会影响CD4+ T细胞的极化和功能，但这是否有助于AZA的疗效目前尚不清楚。通过对73例接受AZA治疗的HR-MDS患者进行功能蛋白质组学、转录组学和突变分析，我们发现，与上调相同通路的无反应者相比，有反应的患者表现出协调的CD4+ T细胞免疫反应，并且在接受AZA治疗后CD4+ T细胞中的炎性细胞因子信号通路下调。我们进一步观察到，AZA介导的CD4+FOXP3-常规T细胞（Tcons）中白细胞介素-6（IL-6）诱导的STAT3磷酸化下调，这与更好的反应和生存独立相关，而它也与患者的突变数量和谱无关。AZA诱导的Tcons中IL-6/STAT3轴下调恢复了CD4+ T细胞亚群中的STAT信号结构，而在Tcons中上调IL-6/STAT3活性的患者中，STAT信号网络仍然紊乱。鉴于CD4+ T细胞在适应性免疫中的关键作用，我们的研究结果表明，Tcons中IL-6/STAT3通路的下调可能构成了AZA一种先前未被认识的免疫介导作用机制，并为开发AZA与IL-6/STAT3轴抑制剂联合使用的合理策略奠定了基础。
