ABO blood group IgM isoagglutinins interact with tumor-associated O-glycan structures in pancreatic cancer

• Published in: Clinical cancer research 2014-12, Vol.20 (23), p.6117-6126
• Main Authors: Hofmann, Bianca T, Stehr, Anne, Dohrmann, Thorsten, Güngör, Cenap, Herich, Lena, Hiller, Jens, Harder, Sönke, Ewald, Florian, Gebauer, Florian, Tachezy, Michael, Precht, Clarissa, Izbicki, Jakob R, Bockhorn, Maximilian, Wagener, Christoph, Wolters-Eisfeld, Gerrit
• Format: Article
• Language: English
• Subjects: ABO Blood-Group System - immunology; Adult; Aged; Agglutinins - blood; Agglutinins - immunology; Agglutinins - metabolism; Carcinoma, Pancreatic Ductal - immunology; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Case-Control Studies; Female; Humans; Immunoglobulin M - blood; Immunoglobulin M - immunology; Immunoglobulin M - metabolism; Male; Middle Aged; Neoplasm Staging; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Polysaccharides - metabolism; Protein Binding; Young Adult
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-14-0716

The ABO gene locus is associated with the risk of developing pancreatic ductal adenocarcinoma (PDAC) resulting in an increased incidence in individuals with non-O blood groups. Up to 90% of PDAC specimens display alterations in mucin type O-GalNAc glycosylation. Because aberrant O-GalNAc glycans (Tn and T antigen) are structurally related to blood group A and B glycans, we investigated the role of IgM isoagglutinins in PDAC. Binding studies of IgM isoagglutinins toward blood group A, B, Tn antigen, and T antigen glycoconjugates from patients with PDAC and healthy individuals were conducted. Isoagglutinin titers and total IgM were compared between patients with PDAC and control group. An anti-A antibody was used for immunoprecipitation of aberrant O-glycosylated tumor proteins and subsequent mass spectromic analysis. We found that IgM isoagglutinins bind blood group antigens, Tn and T glycoconjugates as well as tumor-derived glycoproteins. Blood group A isoagglutinins exhibited a strong binding toward blood group B antigen and T antigen, whereas blood group B showed binding to blood group A antigen and Tn antigen. Furthermore, we confirmed a decreased frequency in individuals with blood group O and observed a significant decrease of IgM isoagglutinin titers in PDAC sera compared with control sera, whereas total IgM levels were unaltered. We identified new PDAC-derived O-GalNAc glycoproteins by mass spectrometry using a blood group A-specific antibody. Our data elucidated a novel interaction of blood group IgM isoagglutinins and PDAC O-GalNAc glycoproteins that may contribute to the pathogenesis and progression of pancreatic cancer.