Endoplasmic reticulum stress induced LOX‐1⁺ CD15⁺ polymorphonuclear myeloid‐derived suppressor cells in hepatocellular carcinoma

Abstract

A recent study indicated that Lectin-type oxidized LDL receptor-1 (LOX-1) was a distinct surface marker for human polymorphisms myeloid-derived suppressor cells (PMN-MDSC). The present study was aimed to investigate the existence LOX-1 PMN-MDSC in hepatocellular carcinoma (HCC) patients. One hundred and twenty-seven HCC patients, 10 patients with mild active chronic hepatitis B, 10 liver cirrhosis due to hepatitis B, 10 liver dysplastic node with hepatitis B and 50 health control were included. LOX-1 CD15 PMN-MDSC were significantly elevated in HCC patients compared with healthy control and patients with benign diseases. LOX-1 CD15 PMN-MDSC in circulation were positively associated with those in HCC tissues. LOX-1 CD15 PMN-MDSCs significantly reduced proliferation and IFN-γ production of T cells with a dosage dependent manner with LOX-1 CD15 PMNs reached negative results. The suppression on T cell proliferation and IFN-γ production was reversed by ROS inhibitor and Arginase inhibitor. ROS level and activity of arginase of LOX-1 CD15 PMN were higher in LOX-1 CD15 PMN-MDSCs than LOX-1 CD15 PMNs, as well as the expression of the NADPH oxidase NOX2 and arginase I. RNA sequence revealed that LOX-1 CD15 PMN-MDSCs displayed significantly higher expression of spliced X-box -binding protein 1 (sXBP1), an endoplasmic reticulum (ER) stress marker. ER stress inducer induced LOX-1 expression and suppressive function for CD15 PMN from health donor. For HCC patients, LOX-1 CD15 PMN-MDSCs were positively related to overall survival. Above all, LOX-1 CD15 PMN-MDSC were elevated in HCC patients and suppressed T cell proliferation through ROS/Arg I pathway induced by ER stress. They presented positive association with the prognosis of HCC patients.

Inflammation and Liver Cancer: Molecular Mechanisms and Therapeutic Targets

“…128 Endoplasmic reticulum stress regulates immune cells by increasing the expression of lectin-type oxidized low-density lipoprotein receptor-1 (LOX-1), a cell surface marker for polymorphonuclear (PMN)-MDSCs. 129 The number of LOX-1 þ CD15 þ PMN-MDSCs were increased in HCC patients and positively associated with the prognosis. 129 ER stress-induced LOX-1 þ CD15 þ PMN-MDSCs suppressed T cell proliferation, implicating them in immune tolerance to tumor cells.…”

“…129 ER stress-induced LOX-1 þ CD15 þ PMN-MDSCs suppressed T cell proliferation, implicating them in immune tolerance to tumor cells. 129 Because ER stress contributes to HCC development, suppression of ER stress could be an HCC treatment option. For example, tauroursodeoxycholic acid, an ER stress reducer, suppressed ER stress-mediated NASH HCC.…”

Recent advances on the crosstalk between neutrophils and B or T lymphocytes

“…It is important to remark that, considering the very low number of circulating and tissue‐derived immunosuppressive neutrophil populations that can be isolated for functional assays, the identification of specific markers identifying pure populations of immunosuppressive neutrophils would definitely help advance the field. Among the candidate markers, lectin‐like oxidized low‐density lipoprotein receptor‐1 has been recently proposed to distinguish immunosuppressive PMN‐MDSCs from normal neutrophils in blood and tissues from cancer patients, as well as in blood from infants . However, these findings require further validation across more laboratories.…”

The specificity and definition of blood eosinophil

“…Various artificial intelligence methods have been applied in the COPDGene and ECLIPSE studies. [3][4][5][6] For example, deep learning with deep belief network has been applied to classify exacerbation frequency in COPDGene. 5 However, the goal of our study was to specifically examine the role of blood eosinophils in AECOPD, because blood eosinophil measurement is a widely available clinical test, and there are potential treatments for eosinophilic COPD.…”

“…[3][4][5][6] For example, deep learning with deep belief network has been applied to classify exacerbation frequency in COPDGene. 5 However, the goal of our study was to specifically examine the role of blood eosinophils in AECOPD, because blood eosinophil measurement is a widely available clinical test, and there are potential treatments for eosinophilic COPD. 7 We show that blood eosinophil levels could provide further risk stratification of AECOPD in patients with COPD with a history of frequent exacerbations.…”