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Modulation of IL-6/...
Modulation of IL-6/STAT3 signaling axis in CD4+FOXP3- T cells represents a potential antitumor mechanism of azacitidine
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Lamprianidou, E (author)
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Kordella, C (author)
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Kazachenka, A (author)
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Zoulia, E (author)
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Bernard, E (author)
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Filia, A (author)
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Laidou, S (author)
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Garantziotis, P (author)
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Vassilakopoulos, TP (author)
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Papageorgiou, SG (author)
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Pappa, V (author)
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Galanopoulos, AG (author)
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Viniou, N (author)
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Nakou, E (author)
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Kalafati, L (author)
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- Chatzidimitriou, A (author)
- Karolinska Institutet
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Kassiotis, G (author)
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Papaemmanuil, E (author)
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Mitroulis, I (author)
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Kotsianidis, I (author)
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(creator_code:org_t)
- 2021-01-06
- 2021
- English.
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In: Blood advances. - : American Society of Hematology. - 2473-9537 .- 2473-9529. ; 5:1, s. 129-142
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http://kipublication...
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https://doi.org/10.1...
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Abstract
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- 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.
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- art (subject category)
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- By the author/editor
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Lamprianidou, E
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Kordella, C
-
Kazachenka, A
-
Zoulia, E
-
Bernard, E
-
Filia, A
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show more...
-
Laidou, S
-
Garantziotis, P
-
Vassilakopoulos, ...
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Papageorgiou, SG
-
Pappa, V
-
Galanopoulos, AG
-
Viniou, N
-
Nakou, E
-
Kalafati, L
-
Chatzidimitriou, ...
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Kassiotis, G
-
Papaemmanuil, E
-
Mitroulis, I
-
Kotsianidis, I
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show less...
- Articles in the publication
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Blood advances
- By the university
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Karolinska Institutet