| Autor: |
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 |
| Zdroj: |
Blood Advances; January 2021, Vol. 5 Issue: 1 p129-142, 14p |
| Abstrakt: |
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. |
| Databáze: |
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