Systemic Monocytic-MDSCs Are Generated from Monocytes and Correlate with Disease Progression in Breast Cancer Patients

Abstract

Myeloid-derived suppressor cells (MDSCs) are highly immunosuppressive myeloid cells, which increase in cancer patients. The molecular mechanism behind their generation and function is unclear. Whereas granulocytic-MDSCs correlate with poor overall survival in breast cancer, the presence and relevance of monocytic-MDSCs (Mo-MDSCs) is unknown. Here we report for the first time an enrichment of functional blood Mo-MDSCs in breast cancer patients before they acquire a typical Mo-MDSC surface phenotype. A clear population of Mo-MDSCs with the typical cell surface phenotype (CD14+HLA-DRlow/-CD86low/-CD80low/-CD163low/-) increased significantly first during disease progression and correlated to metastasis to lymph nodes and visceral organs. Furthermore, monocytes, comprising the Mo-MDSC population, from patients with metastatic breast cancer resemble the reprogrammed immunosuppressive monocytes in patients with severe infections, both by their surface and functional phenotype but also at their molecular gene expression profile. Our data suggest that monitoring the Mo-MDSC levels in breast cancer patients may represent a novel and simple biomarker for assessing disease progression.

Monocytic and granulocytic myeloid derived suppressor cells differentially regulate spatiotemporal tumour plasticity during metastatic cascade

“…MDSC induction and infiltration in mouse mammary tumour models as well as the clinical setting of breast cancer have been previously reported252627. However, the identity of the MDSC subsets in these tumours and their molecular mechanism of interaction with the tumour remain elusive.…”

On the origin of myeloid-derived suppressor cells

“…The molecular mechanism behind monocyte reprogramming, in sepsis as well as in cancer, is suggested to rely on a repeated TLR-signal in combination with certain cytokines or mediators (e.g., IL-10, Wnt5a, and PGE 2 ) thus leading to the formation of immunosuppressive NFκB p50:p50 homodimers instead of pro-inflammatory NFκB p65:p50 heterodimers (Figure 5) [13, 26, 120–122]. TLR-ligands (foremost LPS) are known to induce the expansion and activation of MDSCs [123].…”

Myeloid-derived suppressor cells in gliomas

“…The frequency of MDSCs positively correlates with clinical stage and tumour burden in patients with breast [25], gastric [26], and colorectal cancers [27]. Increased levels of CD14 + HLA-DR –/low MDSCs were correlated with extrathoracic metastasis and poor response to chemotherapy in non-small cell lung cancer patients [28].…”