Enhanced sialylation of bone marrow mesenchymal stromal cells contributes to immune remodeling through macrophage polarization in multiple myeloma patients.
Ruer A, Van Morckhoven D, et al. • Frontiers in immunology • 2026
BM-MSC hypersialylation may contribute to immune remodeling in MM by promoting M2-like macrophage polarization, with MM-MSCs exhibiting significantly higher surface sialylation than healthy donor-, T-MM-, and MGUS-MSCs.
Key Findings
Results
MM-MSCs exhibited significantly higher surface sialylation than MSCs from healthy donors, treated MM patients, and MGUS patients.
Sialic acid quantification was performed on MSCs from four groups: healthy donors (HD), MM patients, treated MM patients (T-MM), and MGUS patients.
The elevated sialylation was specific to active/untreated MM, distinguishing it from treated and pre-malignant conditions.
Siglec ligands were also quantified alongside sialic acids on the MSC surface.
The comparison across four patient groups allowed discrimination of disease-stage-specific glycosylation changes.
Results
MM-MSC sialylation was positively correlated with the percentage of plasma cells and LDH levels in MM patients.
Two clinical parameters were correlated with MSC surface sialylation: bone marrow plasma cell percentage and serum LDH levels.
LDH is a marker of tumor burden and cell turnover in MM.
Plasma cell percentage reflects disease burden in the bone marrow.
The positive correlations suggest that MSC hypersialylation tracks with disease severity.
Results
Direct MSC-plasma cell coculture enhanced MSC hypersialylation more than conditioned medium or transwell coculture, indicating a contact-dependent mechanism.
Three coculture conditions were compared: direct coculture (cell-to-cell contact), conditioned medium (soluble factors only), and transwell coculture (physical separation allowing soluble factor exchange).
Direct coculture produced the greatest increase in MSC sialylation.
This finding indicates that cell-to-cell contact between plasma cells and MSCs is required for maximal sialylation induction.
The result points to a juxtacrine rather than purely paracrine signaling mechanism.
Results
qPCR screening of 84 glycosylation-related genes identified ST6Gal1 and NEU2 as dysregulated genes implicated in the sialylation pathway in MM-MSCs.
A panel of 84 glycosylation-related genes was screened by qPCR.
ST6Gal1 encodes a sialyltransferase that adds sialic acid in alpha-2,6 linkage to galactose residues.
NEU2 encodes a neuraminidase/sialidase involved in sialic acid removal.
Dysregulation of both an enzyme that adds sialic acid (ST6Gal1) and one that removes it (NEU2) is consistent with net hypersialylation in MM-MSCs.
Results
Inflammation and hypoxia were identified as key regulators of Siglec-7 ligand, Siglec-9 ligand, and ST6Gal1 expression by MSCs.
Multiple culture conditions were tested to model the bone marrow microenvironment: myeloma coculture, conditioned medium, hypoxia, inflammation, and 3D culture.
Hypoxia and inflammation specifically upregulated expression of Siglec-7L, Siglec-9L, and ST6Gal1.
Siglec-7 and Siglec-9 are inhibitory receptors expressed on immune cells including NK cells and macrophages.
These findings link known features of the MM bone marrow microenvironment (hypoxia and inflammation) to mechanisms of immune evasion via sialylation.
Results
Increased MSC sialylation promoted an M2-like macrophage phenotype, while inhibition of sialylation shifted macrophages toward an M1-like profile.
M2-like polarization was measured by CD206 expression on macrophages.
M1-like polarization was measured by CD40 and HLA-DR expression.
Sialylation was modulated using both inhibitors and an activator of sialylation.
When MSC sialylation was inhibited, production of M2-associated cytokines was reduced.
These results functionally link MSC hypersialylation to immunosuppressive macrophage polarization in the MM bone marrow microenvironment.
What This Means
This research investigates how bone marrow support cells (called mesenchymal stromal cells, or MSCs) in multiple myeloma (MM) patients have an altered sugar coating on their surface — specifically, they carry more of a sugar called sialic acid than the same cells from healthy people or patients whose disease is controlled. This 'hypersialylation' appears to be driven by direct physical contact between the cancer cells (plasma cells) and the MSCs, and is also amplified by the low-oxygen and inflammatory conditions that characterize the myeloma bone marrow environment. The study identified two specific genes, ST6Gal1 and NEU2, that are abnormally active in these cells and likely explain the sugar coating changes.
The practical consequence of this extra sialic acid is that it alters how the immune system behaves in the bone marrow. Specifically, it pushes immune cells called macrophages into an 'M2' state — a wound-healing, anti-inflammatory mode that helps the tumor survive by suppressing immune attack. When the researchers chemically blocked sialylation on the MSCs, macrophages shifted toward a more anti-tumor 'M1' state and produced fewer immunosuppressive signals. This suggests the sugar coating is not just a passive feature of tumor-associated MSCs but is actively reshaping the immune environment to favor cancer survival.
This research suggests that the sialic acid modifications on bone marrow stromal cells represent a novel mechanism by which multiple myeloma remodels its immune environment, and that targeting this pathway — for example, with sialylation inhibitors — could potentially be a strategy to restore immune surveillance in MM patients. The finding that this effect is reversed in treated patients (T-MM-MSCs) also raises the possibility that monitoring MSC sialylation could provide information about disease status.
Ruer A, Van Morckhoven D, Pieters K, Meuleman N, Lagneaux L, Stamatopoulos B. (2026). Enhanced sialylation of bone marrow mesenchymal stromal cells contributes to immune remodeling through macrophage polarization in multiple myeloma patients.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1919303