Sialylation of CD55 by ST3GAL1 Facilitates Immune Evasion in Cancer

Abstract

Altered glycosylations, which are associated with expression and activities of glycosyltransferases, can dramatically affect the function of glycoproteins and modify the behavior of tumor cells. ST3GAL1 is a sialyltransferase that adds sialic acid to core 1 glycans, thereby terminating glycan chain extension. In breast carcinomas, overexpression of ST3GAL1 promotes tumorigenesis and correlates with increased tumor grade. In pursuing the role of ST3GAL1 in breast cancer using ST3GAL1-siRNA to knockdown ST3GAL1, we identified CD55 to be one of the potential target proteins of ST3GAL1. CD55 is an important complement regulatory protein, preventing cells from complement-mediated cytotoxicity. CD55 had one N-linked glycosylation site in addition to a Ser/Thr-rich domain, which was expected to be heavily O-glycosylated. Detailed analyses of N- and O-linked oligosaccharides of CD55 released from scramble or ST3GAL1 siRNA–treated breast cancer cells by tandem mass spectrometry revealed that the N-glycan profile was not affected by ST3GAL1 silencing. The O-glycan profile of CD55 demonstrated a shift in abundance to nonsialylated core 1 and monosialylated core 2 at the expense of the disialylated core 2 structure after ST3GAL1 silencing. We also demonstrated that O-linked desialylation of CD55 by ST3GAL1 silencing resulted in increased C3 deposition and complement-mediated lysis of breast cancer cells and enhanced sensitivity to antibody-dependent cell-mediated cytotoxicity. These data demonstrated that ST3GAL1-mediated O-linked sialylation of CD55 acts like an immune checkpoint molecule for cancer cells to evade immune attack and that inhibition of ST3GAL1 is a potential strategy to block CD55-mediated immune evasion.

Globo H Is a Promising Theranostic Marker for Intrahepatic Cholangiocarcinoma

“…( 25 , 26 ) We have recently reported that mAbVK9 can mediate CDC. ( 27 ) The finding from this study also indicates that VK9 could induce ADCC against the Globo H–expressing cancer cell line. Moreover, we observed increased NK cells and significant up‐regulation of several NK cell markers in the ICC tumor microenvironment of mAbVK9 treated rats.…”

“…( 25 , 26 ) We have recently reported that mAbVK9 can mediate CDC. ( 27 ) As shown in Supporting Fig. S2 , mAbVK9 induced significant ADCC of GHCer‐pretreated HuCCT1 cells with a mean percent lysis of 42.45% ± 5.1%, as compared with the isotype control of 9.79% ± 3.4% at the E:T ratio of 12.5:1 ( P < 0.05).…”

Prognostic tools and candidate drugs based on plasma proteomics of patients with severe COVID-19 complications

“…Most infected patients were males (n = 91, 91%). The median age [interquartile range (IQR)] of patients with severe COVID-19 disease defined by admission to ICU (47 years), but not mild-moderate patients, was higher than the control groups (vs. 38 [33][34][35][36][37][38][39][40][41][42] years, p < 0.001). The ethnicity distribution in the severe and mild-moderate groups was not significantly different; however, the control group had a higher percentage of the Indian subcontinent ethnicity (p = 0.04).…”

Aberrant Sialylation in Cancer: Biomarker and Potential Target for Therapeutic Intervention?

“…Consistently, inhibition of ST3GAL1 has been proposed as a strategy to block CD55-mediated immune evasion. Mechanistically, authors showed that O-linked desialylation of CD55 by ST3GAL1 silencing results in increased C3 deposition and complement-mediated lysis of breast cancer cells, enhancing sensitivity to antibody-dependent cell-mediated cytotoxicity [ 92 ]. A recent work showed that circulating monocytes that infiltrate the tumor can interact with tumor-derived sialylated structures through the receptors Siglec-7 and Siglec-9 in pancreatic ductal adenocarcinoma.…”