Τίτλος:
Modulation of IL-6/STAT3 signaling axis in CD41FOXP32 T cells represents a potential antitumor mechanism of azacitidine
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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.
Συγγραφείς:
Lamprianidou, E.
Kordella, C.
Kazachenka, A.
Zoulia, E.
Bernard, E.
Filia, A.
Laidou, S.
Garantziotis, P.
Vassilakopoulos, T.P.
Papageorgiou, S.G.
Pappa, V.
Galanopoulos, A.G.
Viniou, N.
Nakou, E.
Kalafati, L.
Chatzidimitriou, A.
Kassiotis, G.
Papaemmanuil, E.
Mitroulis, I.
Kotsianidis, I.
Περιοδικό:
Blood advances
Εκδότης:
American Society of Hematology
Λέξεις-κλειδιά:
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
DOI:
10.1182/bloodadvances.2020002351
