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

By T. Condamine, George A. Dominguez, Je-in Youn, A. Kossenkov, Sridevi Mony, Kevin Alicea-Torres, E. Tcyganov, Ayumi Hashimoto, Yulia Nefedova, Cindy Lin and 20 more. Science immunology, 2016

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PMN-MDSC in cancer patients can be distinguished from neutrophils by a genomic signature and by expression of the LOX-1 receptor. Stressing myeloid-derived suppressor cells in cancer Immunotherapies for cancer have shown promising results in part because they overcome the suppressive effects of the tumor microenvironment on immune cells. Condamine et al. now report that polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) can be distinguished from neutrophils in the same cancer patient by the expression of the lipid metabolism–related molecule lectin-type oxidized LDL receptor-1 (LOX-1). LOX-1–expressing neutrophils were nearly undetectable in healthy individuals but were found prominently in tumor tissues. Moreover, exposing neutrophils from healthy individuals to endoplasmic reticulum stress resulted in up-regulation of LOX-1 and increased suppressive function. These data support the specific targeting of LOX-1–expressing PMN-MDSC for cancer immunotherapy. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are important regulators of immune responses in cancer and have been directly implicated in the promotion of tumor progression. However, the heterogeneity of these cells and the lack of distinct markers hamper the progress in understanding 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. The most prominent changes were observed in the expression of genes associated with endoplasmic reticulum (ER) stress. Unexpectedly, 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 to 15% of total neutrophils in cancer patients and 15 to 50% of neutrophils in tumor tissues were LOX-1+. In contrast to their LOX-1− counterparts, LOX-1+ neutrophils had gene signature, potent immunosuppressive activity, up-regulation of ER stress, and other biochemical characteristics of PMN-MDSCs. Moreover, induction of ER stress in neutrophils from healthy donors up-regulated LOX-1 expression and converted these cells to suppressive PMN-MDSCs. Thus, we identified a specific marker of human PMN-MDSC associated with ER stress and lipid metabolism, which provides new insights into the biology and potential therapeutic targeting of these cells.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/838c4a8019296eb1ec099776ff85c01e0aca6631

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Citations in the corpus

The Tumor Microenvironment Innately Modulates Cancer Progression (2019, background): “In particular, MDSCs enhance tumor cell stemness, increase angiogenesis, and advance the metastatic process by promoting EMT through IL6 secretion (44, 45).”
Myeloid-derived suppressor cells (2017, background): “In these reports, neutrophils with immunosuppressive and tumor-promoting functions are called N2, as opposed to antitumor,N1, neutrophils (8, 9).”
Metabolic Instruction of Immunity (2017, positive): “Expression of lectin-type oxidized LDL receptor 1 (LOX-1) selectively marks MDSCs and oxidized lipid uptake and lipoprotein metabolism contributes to their T cell suppressive functions (Condamine et al., 2016).”
Tumorigenic and Immunosuppressive Effects of Endoplasmic Reticulum Stress in Cancer (2017, positive): “More importantly, pharmacological induction of ER stress using thapsigargin triggered LOX-1 upregulation in human neutrophils and simultaneously transformed them into immunosuppressive cells, a process that could be prevented by targeting IRE1α–XBP1 activation using selective IRE1α inhibitors such a”