The human placenta shapes the phenotype of decidual macrophages.

During human pregnancy, placenta-derived extravillous trophoblasts (EVTs) invade the decidua and communicate with maternal immune cells. The decidua distinguishes into basalis (decB) and parietalis (decP). The latter remains unaffected by EVT invasion. By defining a specific gating strategy, we report the accumulation of macrophages in decB. We describe a decidua basalis-associated macrophage (decBAM) population with a differential transcriptome and secretome compared with decidua parietalis-associated macrophages (decPAMs). decBAMs are CD11chi and efficient inducers of Tregs, proliferate in situ, and secrete high levels of CXCL1, CXCL5, M-CSF, and IL-10. In contrast, decPAMs exert a dendritic cell-like, motile phenotype characterized by induced expression of HLA class II molecules, enhanced phagocytosis, and the ability to activate T cells. Strikingly, EVT-conditioned media convert decPAMs into a decBAM phenotype. These findings assign distinct macrophage phenotypes to decidual areas depending on placentation and further highlight a critical role for EVTs in the induction of decB-associated macrophage polarization.

Tumor-Mediated Neutrophil Polarization and Therapeutic Implications.

Neutrophils are immune cells with reported phenotypic and functional plasticity. Tumor-associated neutrophils display many roles during cancer progression. Several tumor microenvironment (TME)-derived factors orchestrate neutrophil release from the bone marrow, recruitment and functional polarization, while simultaneously neutrophils are active stimulators of the TME by secreting factors that affect immune interactions and subsequently tumor progression. Successful immunotherapies for many cancer types and stages depend on the targeting of tumor-infiltrating lymphocytes. Neutrophils impact the success of immunotherapies, such as immune checkpoint blockade therapies, by displaying lymphocyte suppressive properties. The identification and characterization of distinct neutrophil subpopulations or polarization states with pro- and antitumor phenotypes and the identification of the major TME-derived factors of neutrophil polarization would allow us to harness the full potential of neutrophils as complementary targets in anticancer precision therapies.

The fate of human SUSD2+ endometrial mesenchymal stem cells during decidualization.

Regeneration of the endometrial stromal compartment in premenopausal women is likely maintained by the perivascular endometrial mesenchymal stem/stromal cells (eMSC) expressing sushi domain containing 2 (SUSD2). The fate of SUSD2+ eMSC during pregnancy and their role in decidualization is not fully known. The aim of our study was to determine the effect of progesterone on the stemness of the SUSD2+ eMSC isolated from non-pregnant uterine samples. Secondary objectives were to characterize the functional capacity including differentiation and clonogenicity assays of SUSD2+ eMSC isolated from decidua at full term and compare it to the capacity of those isolated from non-pregnant uterine samples. Progesterone treatment induced changes in the decidual gene expression profile in non-pregnant SUSD2+ eMSC. Data analysis of a publicly available single cell RNA-seq data set revealed differential expression of several mesenchymal and epithelial signature genes between the SUSD2+ eMSC and the decidual stromal cells, suggesting mesenchymal-to-epithelial transition occurs during decidualization. Histological analysis revealed a significantly lower abundance of SUSD2+ eMSC in 1st trimester and full term samples compared to non-pregnant samples, p = 0.0296 and 0.005, respectively. The differentiation and the colony forming capacity did not differ significantly between the cells isolated from non-pregnant and pregnant uterine samples. Our results suggest that SUSD2+ eMSC undergo decidualization in vitro, while maintaining MSC plasma membrane phenotype. Human eMSC seem to play an important role in the course of endometrial decidualization and embryo implantation. Pregnancy reduced the abundance of SUSD2+ eMSC, however eMSC function remains intact.

Myeloperoxidase: Growing importance in cancer pathogenesis and potential drug target.

Myeloperoxidase is a heme-peroxidase which makes up approximately 5% of the total dry cell weight of neutrophils where it is predominantly found in the primary (azurophilic) granules. Other cell types, such as monocytes and certain macrophage subpopulations also contain myeloperoxidase, but to a much lesser extent. Initially, the function of myeloperoxidase had been mainly associated with its ability as a catalyzer of reactive oxidants that help to clear pathogens. However, over the past years non-canonical functions of myeloperoxidase have been described both in health and disease. Attention has been specially focused on inflammatory diseases, in which an exacerbate infiltration of leukocytes can favor a poorly-controlled production and release of myeloperoxidase and its oxidants. There is compelling evidence that myeloperoxidase derived oxidants contribute to tissue damage and the development and propagation of acute and chronic vascular inflammation. Recently, neutrophils have attracted much attention within the large diversity of innate immune cells that are part of the tumor microenvironment. In particular, neutrophil-derived myeloperoxidase may play an important role in cancer development and progression. This review article aims to provide a comprehensive overview of the roles of myeloperoxidase in the development and progression of cancer. We propose future research approaches and explore prospects of inhibiting myeloperoxidase as a strategy to fight against cancer.

Identification of Novel Low-Density Neutrophil Markers Through Unbiased High-Dimensional Flow Cytometry Screening in Non-Small Cell Lung Cancer Patients.

Neutrophils have been described as a phenotypically heterogeneous cell type that possess both pro- and anti-tumor properties. Recently, a subset of neutrophils isolated from the peripheral blood mononuclear cell (PBMC) fraction has been described in cancer patients. These low-density neutrophils (LDNs) show a heterogeneous maturation state and have been associated with pro-tumor properties in comparison to mature, high-density neutrophils (HDNs). However, additional studies are necessary to characterize this cell population. Here we show new surface markers that allow us to discriminate between LDNs and HDNs in non-small cell lung cancer (NSCLC) patients and assess their potential as diagnostic/prognostic tool. LDNs were highly enriched in NSCLC patients (median=20.4%, range 0.3-76.1%; n=26) but not in healthy individuals (median=0.3%, range 0.1-3.9%; n=14). Using a high-dimensional human cell surface marker screen, we identified 12 surface markers that were downregulated in LDNs when compared to HDNs, while 41 surface markers were upregulated in the LDN subset. Using flow cytometry, we confirmed overexpression of CD36, CD41, CD61 and CD226 in the LDN fraction. In summary, our data support the notion that LDNs are a unique neutrophil population and provide novel targets to clarify their role in tumor progression and their potential as diagnostic and therapeutic tool.