Modulation of IL-6/STAT3 signaling axis in CD4(+)FOXP3(-) T cells represents a potential antitumor mechanism of azacitidine Journal Article
| Authors: | 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. |
| Article Title: | Modulation of IL-6/STAT3 signaling axis in CD4(+)FOXP3(-) T cells represents a potential antitumor mechanism of azacitidine |
| 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. |
| Keywords: | signal transduction; controlled study; protein phosphorylation; treatment response; aged; survival analysis; human cell; major clinical study; drug dose reduction; protein function; transcription factor foxp3; stat3 protein; multiple cycle treatment; cohort analysis; antineoplastic activity; mutational analysis; proteomics; transcriptomics; high risk patient; myelodysplastic syndrome; cellular immunity; cd4+ t lymphocyte; interleukin 6; down regulation; upregulation; adaptive immunity; t lymphocyte subpopulation; azacitidine; lymphocyte function; human; male; female; priority journal; article; lymphocyte structure |
| Journal Title: | Blood Advances |
| Volume: | 5 |
| Issue: | 1 |
| ISSN: | 2473-9529 |
| Publisher: | American Society of Hematology |
| Date Published: | 2021-01-12 |
| Start Page: | 129 |
| End Page: | 142 |
| Language: | English |
| DOI: | 10.1182/bloodadvances.2020002351 |
| PROVIDER: | scopus |
| PMCID: | PMC7805308 |
| PUBMED: | 33570632 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 February 2021 -- Source: Scopus |
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