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

ABSTRACT: Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) are important regulators of immune responses and promoters of tumor progression in cancer1,2. The heterogeneity of these cells as well as their distinction from neutrophils hampers the progress in understanding of the biology and clinical significance of these cells. PMN-MDSC had a distinct gene signature from neutrophils isolated from the same patients with most prominent changes in genes associated with endoplasmic reticulum (ER) stress response. Surprisingly, low-density lipoprotein (LDL) was one of the most enriched gene regulators and 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 expressed in only 0.7% of neutrophils in peripheral blood of healthy donors, whereas 5-15% of 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, biochemical and functional characteristics of PMN-MDSC. Induction of ER stress in neutrophils from healthy donors up-regulated LOX-1 expression and converted these cells to suppressive PMN-MDSC. Thus, PMN-MDSC have distinct gene signature and LOX-1 can define this population of cells, which may provide new insight to the biology and clinical evaluation of these cells. Examination of LOX1+/LOX1- and PMN/MDSC cells in cancer patient samples

ORGANISM(S): Homo sapiens

SUBMITTER: Priyankara Wickramasinghe

PROVIDER: E-GEOD-79404 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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

Project description:Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) are important regulators of immune responses and promoters of tumor progression in cancer1,2. The heterogeneity of these cells as well as their distinction from neutrophils hampers the progress in understanding of the biology and clinical significance of these cells. PMN-MDSC had a distinct gene signature from neutrophils isolated from the same patients with most prominent changes in genes associated with endoplasmic reticulum (ER) stress response. Surprisingly, low-density lipoprotein (LDL) was one of the most enriched gene regulators and 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 expressed in only 0.7% of neutrophils in peripheral blood of healthy donors, whereas 5-15% of 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, biochemical and functional characteristics of PMN-MDSC. Induction of ER stress in neutrophils from healthy donors up-regulated LOX-1 expression and converted these cells to suppressive PMN-MDSC. Thus, PMN-MDSC have distinct gene signature and LOX-1 can define this population of cells, which may provide new insight to the biology and clinical evaluation of these cells.

2016-07-22 | GSE79404 | GEO

Fatty acid transporter 2 regulates lipid metabolism and suppressive function of neutrophils in cancer

Project description:Polymorphonuclear myeloid derived suppressor cells (PMN-MDSC) are pathologically activated neutrophils that accumulate in cancer and many other pathologic conditions. PMN-MDSC are critically important for the regulation of immune responses in cancer, promotion of tumor progression, and metastases. Despite the recent advances in understanding of the PMN-MDSC biology, the mechanisms responsible for pathological activation of neutrophils are not well defined, which limit selective targeting of PMN-MDSC. Here, we report that mouse and human PMN-MDSC exclusively up-regulate fatty acid transporter protein 2 (FATP2). Over-expression of FATP2 in PMN-MDSC was controlled by GM-CSF, through the activation of STAT5 transcription factor. Genetic ablation of FATP2 abrogated the suppressive activity of PMN-MDSC in spleens and tumors. FATP2 in neutrophils promoted accumulation of oxidized lipids. However, the main mechanism of FATP2 mediated suppressive activity of PMN-MDSC involved uptake of arachidonic acid and synthesis of prostaglandin E2. The selective pharmacological inhibition of FATP2 abrogated activity of PMN-MSC and substantially delayed tumor progression. In combination with check-point inhibitors it blocked tumor progression in mice. Thus, FATP2 mediates acquisition of immune suppressive activity by PMN-MDSC and represents a new target to inhibit the functions of PMN-MDSC and improve the effect of immunotherapy of cancer.

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Deletion of LOX-1 has protective effects on ischemic brain damage in the genetic background of stroke-prone spontaneously hypertensive rat

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2020-05-19 | E-MTAB-8389 | biostudies-arrayexpress

Deletion of LOX-1 has protective effects on ischemic brain damage in the genetic background of stroke-prone spontaneously hypertensive rat

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2020-04-15 | GSE98335 | GEO

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2018-08-31 | GSE69834 | GEO

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