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.