Differential expansion of circulating human MDSC subsets in patients with cancer, infection and inflammation

Abstract

BackgroundMyeloid-derived suppressor cells (MDSC) are a functional myeloid cell subset that includes myeloid cells with immune suppressive properties. The presence of MDSC has been reported in the peripheral blood of patients with several malignant and non-malignant diseases. So far, direct comparison of MDSC across different diseases and Centers is hindered by technical pitfalls and a lack of standardized methodology. To overcome this issue, we formed a network through the COST Action Mye-EUNITER (www.mye-euniter.eu) with the goal to standardize and facilitate the comparative analysis of human circulating MDSC in cancer, inflammation and infection. In this manuscript, we present the results of the multicenter study Mye-EUNITER MDSC Monitoring Initiative, that involved 13 laboratories and compared circulating MDSC subsets across multiple diseases, using a common protocol for the isolation, identification and characterization of these cells.MethodsWe developed, tested, executed and optimized a standard operating procedure for the isolation and immunophenotyping of MDSC using blood from healthy donors. We applied this procedure to the blood of almost 400 patients and controls with different solid tumors and non-malignant diseases. The latter included viral infections such as HIV and hepatitis B virus, but also psoriasis and cardiovascular disorders.ResultsWe observed that the frequency of MDSC in healthy donors varied substantially between centers and was influenced by technical aspects such as the anticoagulant and separation method used. Expansion of polymorphonuclear (PMN)-MDSC exceeded the expansion of monocytic MDSC (M-MDSC) in five out of six solid tumors. PMN-MDSC expansion was more pronounced in cancer compared with infection and inflammation. Programmed death-ligand 1 was primarily expressed in M-MDSC and e-MDSC and was not upregulated as a consequence of disease. LOX-1 expression was confined to PMN-MDSC.ConclusionsThis study provides improved technical protocols and workflows for the multi-center analysis of circulating human MDSC subsets. Application of these workflows revealed a predominant expansion of PMN-MDSC in solid tumors that exceeds expansion in chronic infection and inflammation.

Cancer Cells Resistance Shaping by Tumor Infiltrating Myeloid Cells

“…For example M-MDSC are S100a9 high , whilst mature monocytes are S100a9 low [ 169 , 170 ]. In the human PMN population, the LOX1 marker turned out to be expressed on PMN-MDSC in contrast to mature neutrophils [ 171 , 172 ]. Additional to the phenotypic features detailed above, mouse studies showed that CD84 expressed on PMN-MDSC helps to distinguish them from neutrophils [ 173 ].…”

“…Indeed, MDSC can constitute up to 51% of non-epithelial cells in Pancreatic Ductal Adenocarcinoma (PDAC) when compared to 5% in non-invasive Intraductal Papillary Mucinous Neoplasms (IPMNs) correlated with a loss of cytotoxic T cells in early lesions and a gain of immunosuppressive myeloid populations in progressing diseases. A multicenter analysis showed that PMN-MDSC are a leading population of MDSC in solid tumors and their expansion is especially intensified in the context of tumorigenesis when compared to other inflammatory states [ 172 ]. Interestingly, mouse research showed that, in TAM rich tumors, M-CSF/M-CSFR signaling indirectly blocks the recruitment of PMN-MDSC to the tumor site.…”

Determinants, mechanisms, and functional outcomes of myeloid cell diversity in cancer

“…117 These data suggest that type 2 immunity could be mobilized for cancer therapy in some settings and highlight the complexity and functional plasticity of TME components. 128 In other studies, PGE 2 was found to support the differentiation of myeloid cells with immune modulatory and tumor-supporting capacities (often referred to as myeloid-derived suppressor cells, or MDSCs) 130,131 via the epigenetic and chromatin actions of DNA methyltransferase 3A (DNMT3A) and p50 nuclear factor (NF)-κB TF, respectively. 132,133 Accumulating evidence highlight the role of PGE 2 in controlling the tumor-promoting activities of neutrophils.…”

“…[200][201][202][203] Some populations of cancer-elicited neutrophils, also referred to as granulocytic (G)-MDSCs, are immune suppressive and can limit T-cell activation, but their properties are incompletely characterized due the absence of unequivocal markers for prospective isolation. 130,131,204 At least to some extent, immature bone marrow neutrophils display features ascribed to G-MDSCs, including low buoyant cell density or expression of ARG1, lectin-like oxidized low-density lipoprotein receptor (LOX)1 or FATP2, among others. 134,201,[205][206][207][208] In this context, a recent scRNA-Seq study in breast cancer models suggested that the acquisition of immune suppressive and tumor-promoting properties may rely on aberrant differentiation of neutrophil progenitors.…”

Myeloid-Derived Suppressor Cell Differentiation in Cancer: Transcriptional Regulators and Enhanceosome-Mediated Mechanisms

“…While these cells possess many phenotypic and morphological hallmarks of anti-tumor myeloid-lineage cells like monocytes and neutrophils, they differ significantly in their activation programs and function to inhibit anti-tumor immunity by producing immunosuppressive factors like arginase, nitrogen species and reactive oxygen species, among others ( 10 , 17 – 19 ). MDSCs are a significant obstacle to immunotherapies including checkpoint inhibitors; accumulation of MDSCs populations within circulating and tumor-infiltrating leukocytes have been observed in patients who fail to respond to checkpoint inhibitor therapy ( 18 , 19 ).…”