S100A4 mediates the accumulation and functions of myeloid-derived suppressor cells via GP130/JAK2/STAT3 signaling in acute myeloid leukemia

Acute myeloid leukemia (AML) is an immunosuppressive hematologic malignancy with a poor prognosis. An immunosuppressive microenvironment blunts AML therapy. However, the prognostic and therapeutic roles of the factors that mediate immunosuppression in AML remain elusive. S100 calcium-binding protein A4 (S100A4) was identified as an immunosuppression-mediating factor by analyzing The Cancer Genome Atlas AML project (TCGA-LAML) transcriptome data and data from AML-bearing mice and AML patients. The S100A4-mediated signaling pathway in myeloid-derived suppressor cells (MDSCs) was evaluated. Elevated S100A4 expression was positively associated with worse survival of AML patients, MDSCs, macrophages and immune checkpoints. S100A4 silencing downregulated the expression levels of MDSC-associated CD14, CCR2 and CCL2, reduced MDSC expansion and impaired MDSC-mediated inhibition of T cell activation and proliferation. S100A4-based prognostic signature (SPS) was an independent risk factor for AML patients. The high-risk group based on SPS was not only associated with adverse survival, MDSCs and macrophages and immune checkpoints but also insensitive to 25 chemotherapy drugs. It was also found that CCAAT enhancer binding protein beta (CEBPB) mediated S100A4 transcription. CEBPB silencing downregulated the expression levels of MDSC-associated CD14, CCR2 and CCL2. Mechanistically, S100A4 activated GP130/JAK2/STAT3 signaling in MDSCs by interacting with the cytokine-binding domain of GP130. Moreover, S100A4 mediated MDSC expansion through JAK2/STAT3 signaling. This study uncovers the critical role of S100A4 in MDSC accumulation, and S100A4-based prognostic signature may guide chemotherapy sensitivity in patients with AML. [Display omitted] •S100A4 is elevated in AML blasts and positively associated with poor survival of AML patients and immunosuppression.•Eleavted S100A4 positively correlates myeloid derived suppressor cells (MDSCs) and several immune checkpoints.•S100A4-based prognostic signature predicts immunosuppression and the insensitivity to chemodrugs.•S100A4 activates GP130/JAK2/STAT3 pathway to promote MDSC accumulation and functions in AML via interacting GP130.•CEBPB positively regulates S100A4 expression as a transcription factor and mediates several MDSC-related markers.