@article{3102908,
    title = "Modulation of IL-6/STAT3 signaling axis in CD41FOXP32 T cells represents a potential antitumor mechanism of azacitidine",
    author = "Lamprianidou, E. and Kordella, C. and Kazachenka, A. and Zoulia, E. and Bernard, E. and Filia, A. and Laidou, S. and Garantziotis, P. and Vassilakopoulos, T.P. and Papageorgiou, S.G. and Pappa, V. and Galanopoulos, A.G. and Viniou, N. and Nakou, E. and Kalafati, L. and Chatzidimitriou, A. and Kassiotis, G. and Papaemmanuil, E. and Mitroulis, I. and Kotsianidis, I.",
    journal = "Blood advances",
    year = "2021",
    volume = "5",
    number = "1",
    pages = "129-142",
    publisher = "American Society of Hematology",
    doi = "10.1182/bloodadvances.2020002351",
    keywords = "azacitidine;  interleukin 6;  STAT3 protein;  transcription factor FOXP3, adaptive immunity;  aged;  antineoplastic activity;  Article;  CD4+ T lymphocyte;  cellular immunity;  cohort analysis;  controlled study;  down regulation;  drug dose reduction;  female;  high risk patient;  human;  human cell;  lymphocyte function;  lymphocyte structure;  major clinical study;  male;  multiple cycle treatment;  mutational analysis;  myelodysplastic syndrome;  priority journal;  protein function;  protein phosphorylation;  proteomics;  signal transduction;  survival analysis;  T lymphocyte subpopulation;  transcriptomics;  treatment response;  upregulation",
    abstract = "CD+1 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 CD+1 T-cell differentiation and polarization, and perturbed STAT signaling networks in CD+1 T cells subvert antitumor immunity in malignancies. Azacitidine (AZA), the mainstay therapy for high-risk myelodysplastic syndromes (HR-MDS), affects CD+1 T-cell polarization and function, but whether this contributes to AZA efficacy is currently unknown. By using functional proteomic, transcriptomic, andmutational analyses in 73 HR-MDS patients undergoing AZA therapy, we demonstrate that responding patients exhibited a coordinated CD+1 T-cell immune response and downregulated the inflammatory cytokine signaling pathways in CD+1 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 CD+1FOXP32 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 CD+1 T-cell subsets, whereas STAT signaling networks remained disorganized in patients who upregulated IL-6/STAT3 activity in Tcons. Given the pivotal role of CD+1 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-mediatedmechanism of action of AZA and sets the scene for developing rational strategies of AZA combinations with IL-6/STAT3 axis inhibitors. © 2021 by The American Society of Hematology."
}