Modulation of IL-6/STAT3 signaling axis in CD4+FOXP3- T cells represents a potential antitumor mechanism of azacitidine

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, andmutational 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.

Automated summary

CD4(+) T cells play a crucial role in immune responses and tumor immunity. A study on patients with high-risk myelodysplastic syndromes undergoing Azacitidine therapy revealed that responders showed a coordinated immune response in CD4(+) T cells, downregulating inflammatory cytokine signaling pathways, particularly IL-6-induced STAT3 phosphorylation in conventional T cells (Tcons). This downregulation was associated with better response and survival, highlighting a potential immune-mediated mechanism of Azacitidine.