Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients

Abstract

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) are important regulators of immune responses in cancer and have been directly implicated in promotion of tumor progression. However, the heterogeneity of these cells and lack of distinct markers hampers the progress in understanding of the biology and clinical importance of these cells. Using partial enrichment of PMN-MDSC with gradient centrifugation we determined that low density PMN-MDSC and high density neutrophils from the same cancer patients had a distinct gene profile. Most prominent changes were observed in the expression of genes associated with endoplasmic reticulum (ER) stress. Surprisingly, low-density lipoprotein (LDL) was one of the most increased regulators and its receptor oxidized LDL receptor 1 OLR1 was one of the most overexpressed genes in PMN-MDSC. Lectin-type oxidized LDL receptor 1 (LOX-1) encoded by OLR1 was practically undetectable in neutrophils in peripheral blood of healthy donors, whereas 5–15% of total neutrophils in cancer patients and 15–50% of neutrophils in tumor tissues were LOX-1+. In contrast to their LOX-1− counterparts, LOX-1+ neutrophils had gene signature, potent immune suppressive activity, up-regulation of ER stress, and other biochemical characteristics of PMN-MDSC. Moreover, induction of ER stress in neutrophils from healthy donors up-regulated LOX-1 expression and converted these cells to suppressive PMN-MDSC. Thus, we identified a specific marker of human PMN-MDSC associated with ER stress and lipid metabolism, which provides new insight to the biology and potential therapeutic targeting of these cells.

Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors

“…6H). Since we have recently identified LOX-1 as a marker of human PMN-MDSC, which allows for detection of these cells in tumor tissues using immune fluorescent microscopy (Condamine et al, 2016), we then tested the clinical significance of LOX-1 + CD15 + PMN-MDSC in tissue microarray (TMA) obtained from patients with head and neck cancer. The presence of PMN-MDSC was significantly associated with shorter survival in these patients (Fig.…”

Low-Density Lipoprotein Uptake Inhibits the Activation and Antitumor Functions of Human Vγ9Vδ2 T Cells

“…Alterations in de novo lipid biosynthesis are associated with cancer pathogenesis (35). Uptake of exogenous lipids by tumor cells and by nonmalignant cells in the tumor microenvironment may also contribute to malignancy (36)(37)(38). This particular metabolic feature may explain the association of some cancers, including breast cancer, with diets high in fat or cholesterol (39).…”

Unfolding anti-tumor immunity: ER stress responses sculpt tolerogenic myeloid cells in cancer

“…While there is a clear interaction between the induction of ER stress and the metabolic reprogramming of myeloid cells in tumors, it remains unknown whether the tolerogenic effects induced by the accumulation of lipids in myeloid cells are solely mediated through IRE1α-XBP1 signaling or whether additional mediators participate in this process. Nevertheless, recent studies by Gabrilovich and colleagues have elegantly reinforced the crucial immunoregulatory role of aberrant IRE1α-XBP1 signaling in human cancer-associated myeloid cells [85]. In diverse human cancer specimens, upregulation of ER stress-related gene signatures and surface expression of the lectin-type oxidized LDL receptor-1 (LOX-1) distinguished high-density neutrophils from low-density immunosuppressive polymorphonuclear MDSCs (PMN-MDSCs).…”