Bisecting GlcNAc expression by bone marrow stromal cells modulates TGF-β1-driven macrophage polarization in myeloid leukemias

There has been growing evidence highlighting the critical role of tumor-associated macrophages (TAM) in promoting immune evasion and disease progression in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Combined single- cell RNA sequencing, flow cytometry, and immunohistochemistry studies of the innate immune compartment in bone marrow of MDS/AML reveal a shift toward a tumor-supportive M2-polarized macrophage as well as the expression of programmed cell death-ligand 1 (PD-L1) in this cell lineage. We found leukemic stroma cells with a high level of TGFβ1 secretion can determine TAM toward M2-polarized subtype. Further mechanistic investigations revealed that bone marrow (BM) stromal cells with specific glycans, reduced bisecting N-acetylglucosamine (GlcNAc) levels, in MDS/AML promoted M2-polarized subtype through the secretion of TGFβ1, which elevated PD-L1 expression and thereby impaired CD8+ T-cell function. Our study provides insights into the mechanisms of selectively modifying specific glycans in BM stroma cells and how these may contribute to targeting strategies aimed at the tumor microenvironment.