IgG Glycome in Colorectal Cancer

Abstract

Purpose: Alternative glycosylation has significant structural and functional consequences on IgG and consequently also on cancer immunosurveillance. Because of technological limitations, the effects of highly heritable individual variations and the differences in the dynamics of changes in IgG glycosylation on colorectal cancer were never investigated before.Experimental Design: Using recently developed highthroughput UPLC technology for IgG glycosylation analysis, we analyzed IgG glycome composition in 760 patients with colorectal cancer and 538 matching controls. Effects of surgery were evaluated in 28 patients sampled before and three times after surgery. A predictive model was built using regularized logistic regression and evaluated using a 10-cross validation procedure. Furthermore, IgG glycome composition was analyzed in 39 plasma samples collected before initial diagnosis of colorectal cancer. Results:We have found that colorectal cancer associates with decrease in IgG galactosylation, IgG sialylation and increase in core-fucosylation of neutral glycans with concurrent decrease of core-fucosylation of sialylated glycans. Although a model based on age and sex did not show discriminative power (AUC ¼ 0.499), the addition of glycan variables into the model considerably increased the discriminative power of the model (AUC ¼ 0.755). However, none of these differences were significant in the small set of samples collected before the initial diagnosis.Conclusions: Considering the functional relevance of IgG glycosylation for both tumor immunosurveillance and clinical efficacy of therapy with mAbs, individual variation in IgG glycosylation may turn out to be important for prediction of disease course or the choice of therapy, thus warranting further, more detailed studies of IgG glycosylation in colorectal cancer.

Hallmarks of glycosylation in cancer

“…For example, the alteration of cell surface glycans can modulate siglec-7 mediated cytotoxicity of NK cells and contribute to immune evasion [151]. Glycosylation of IgG is known to play a role in tumour immune surveillance and is being investigated as a diagnostic marker in several cancer types [152–155]. Targeting altered glycosylation using anticancer vaccines that target tumour associated antigens is an appealing option for cancer treatment [156, 157].…”

Selectin Ligands Sialyl-Lewis a and Sialyl-Lewis x in Gastrointestinal Cancers

“…For example, pancreatic ductal adenocarcinomas are associated with increased α1,3fucosylation of α1-acid glycoprotein, which is of hepatic origin [102], while colorectal cancers are associated with altered core-fucosylation of IgG glycans, which are produced by plasma cells [103]. In particular, the core-fucosylation was increased in non-sialylated IgG glycans and decreased in those sialylated.…”

Antibody Panel Based N‐Glycan Imaging for N‐Glycoprotein Biomarker Discovery

“…The majority of serum N ‐glycan methods focus on the analysis of a pool of N ‐glycans released from all proteins in the serum (Gornik et al., ; Kirmiz et al., ; Novokmet et al., ; Reiding et al., ; Ruhaak et al., ; Ruhaak, Xu, Li, Goonatilleke, & Lebrilla, ), or the analysis of one target protein's N ‐glycan profile (Comunale et al., ; Pompach et al., ; Ruhaak et al., , ; Shubhakar et al., ; Simunovic et al., ; Šimurina et al., ; Theodoratou et al., ; Zhang et al., ). Pooled serum analyses have shown trends in overall N ‐glycan changes in the presence of cancer, such as increased fucosylation, branching, and bisects (Gebrehiwot et al., ; Hecht et al., ; Snyder et al., ; Vučković et al., ).…”

“…Current Protocols in Protein Science 2014; Reiding et al, 2019;Ruhaak et al, 2008;Ruhaak, Xu, Li, Goonatilleke, & Lebrilla, 2018), or the analysis of one target protein's N-glycan profile (Comunale et al, 2010;Pompach et al, 2016;Ruhaak et al, 2013Ruhaak et al, , 2018Shubhakar et al, 2016;Simunovic et al, 2019;Šimurina et al, 2018;Theodoratou et al, 2016;Zhang et al, 2016). Pooled serum analyses have shown trends in overall N-glycan changes in the presence of cancer, such as increased fucosylation, branching, and bisects (Gebrehiwot et al, 2019;Hecht et al, 2015;Snyder et al, 2016;Vučković et al, 2016).…”