CD115- monocytic myeloid-derived suppressor cells are precursors of OLFM4high polymorphonuclear myeloid-derived suppressor cells

Myeloid-derived suppressor cells (MDSCs) consist of monocytic (M-) MDSCs and polymorphonuclear (PMN-) MDSCs that contribute to an immunosuppressive environment in tumor-bearing hosts. However, research on the phenotypic and functional heterogeneity of MDSCs in tumor-bearing hosts and across different disease stage is limited. Here we subdivide M-MDSCs based on CD115 expression and report that CD115(-) M-MDSCs are functionally distinct from CD115(+) M-MDSCs. CD115(-) M-MDSCs increased in bone marrow and blood as tumors progressed. Transcriptome analysis revealed that CD115(-) M-MDSCs expressed higher levels of neutrophil-related genes. Moreover, isolated CD115(-) M-MDSCs had higher potential to be differentiated into PMN-MDSCs compared with CD115(+) M-MDSCs. Of note, CD115(-) M-MDSCs were able to differentiate into both olfactomedin 4 (OLFM4)(hi) and OLFM4(lo) PMN-MDSCs, whereas CD115(+) M-MDSCs differentiated into a smaller proportion of OLFM4(lo) PMN-MDSCs. In vivo, M-MDSC to PMN-MDSC differentiation occurred most frequently in bone marrow while M-MDSCs preferentially differentiated into tumor-associated macrophages in the tumor mass. Our study reveals the presence of previously unrecognized subtypes of CD115(-) M-MDSCs in tumor-bearing hosts and demonstrates their cellular plasticity during tumorigenesis. CD115(-) monocytic MDSCs, functionally distinct from CD115(+) monocytic MDSCs, increase in the blood and bone marrow as tumor progresses and can give rise to OLFM4(hi) polymorphonuclear MDSCs outside the tumor mass.

Automated summary

This study explores the phenotypic and functional heterogeneity of myeloid-derived suppressor cells (MDSCs) in tumor-bearing hosts. It identifies CD115(-) monocytic MDSCs as a distinct subtype with the potential to differentiate into OLFM4(hi) polymorphonuclear MDSCs. CD115(-) monocytic MDSCs increase in the blood and bone marrow as tumors progress, while preferentially differentiating into tumor-associated macrophages in the tumor mass.