TY - JOUR
TI - Modulation of IL-6/STAT3 signaling axis in CD41FOXP32 T cells represents a potential antitumor mechanism of azacitidine
AU - Lamprianidou, E.
AU - Kordella, C.
AU - Kazachenka, A.
AU - Zoulia, E.
AU - Bernard, E.
AU - Filia, A.
AU - Laidou, S.
AU - Garantziotis, P.
AU - Vassilakopoulos, T.P.
AU - Papageorgiou, S.G.
AU - Pappa, V.
AU - Galanopoulos, A.G.
AU - Viniou, N.
AU - Nakou, E.
AU - Kalafati, L.
AU - Chatzidimitriou, A.
AU - Kassiotis, G.
AU - Papaemmanuil, E.
AU - Mitroulis, I.
AU - Kotsianidis, I.
JO - Blood advances
PY - 2021
VL - 5
TODO - 1
SP - 129-142
PB - American Society of Hematology
SN - null
TODO - 10.1182/bloodadvances.2020002351
TODO - 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
TODO - 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.
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