Phosphorylated alpha-enolase induces autoantibodies in HLA-DR8 pancreatic cancer patients and triggers HLA-DR8 restricted T-cell activation.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the fourth cause of cancer-induced death in the Western World. In PDAC patients, alpha-enolase (ENOA), a glycolytic enzyme that also acts as plasminogen receptor, is up-regulated and elicits the production of autoantibodies. Our previous studies revealed that most PDAC patients specifically produce antibodies to Serine(419)phosphorylated ENOA (Ser(419)P-ENOA) isoforms (ENOA1,2), and that this humoral response correlates with a better clinical outcome. Since autoantibody production can be influenced by HLA polymorphisms, and the ENOA sequence presents multiple peptides predicted to preferentially bind HLA-DR molecules, including the peptide containing Ser(419), we hypothesized that the presence of autoantibodies against ENOA1,2 is associated with specific HLA-DRB1 alleles. Here, we demonstrate that the HLA-DRB1*08 allele is significantly more frequent in PDAC patients with autoantibodies to ENOA1,2 (ENOA1,2(+), 8%) compared to healthy controls (3%, p=0.0112). We observed that a Ser(419)P-ENOA peptide, bioinformatically predicted to bind with high affinity to the HLA-DR8 allele coded by HLA-DRB1*08:01 or *08:04 alleles, was able to activate specific CD4(+) T cell clones derived from a HLA-DRB1*08:01. Thus complexes of the Ser(419)P-ENOA peptide with the HLA that trigger T-cell signaling might be relevant for induction of anti-tumor immune response.

• Authors: Michela Capello, Cristiana Caorsi, Pablo Josè Bogantes Hernandez, Ennia Dametto, Francesca Eleonora Bertinetto, Paola Magistroni, Sabina Rendine, Antonio Amoroso, Francesco Novelli
• Journal: Immunology letters (Immunol Lett) Vol. 167 Issue 1 Pg. 11-6 (Sep 2015) ISSN: 1879-0542 [Electronic] Netherlands
• PMID: 26096821 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

Chemical References

• Autoantibodies
• Biomarkers, Tumor
• DNA-Binding Proteins
• HLA-DR Serological Subtypes
• HLA-DR8 antigen
• HLA-DRB1 Chains
• Ligands
• Peptides
• Tumor Suppressor Proteins
• ENO1 protein, human
• Phosphopyruvate Hydratase

Topics

• Alleles
• Autoantibodies (immunology)
• Biomarkers, Tumor (chemistry, immunology, metabolism)
• Carcinoma, Pancreatic Ductal (genetics, immunology, metabolism)
• Case-Control Studies
• DNA-Binding Proteins (chemistry, immunology, metabolism)
• Gene Frequency
• HLA-DR Serological Subtypes (genetics, immunology, metabolism)
• HLA-DRB1 Chains (genetics)
• Humans
• Ligands
• Lymphocyte Activation (immunology)
• Pancreatic Neoplasms (genetics, immunology, metabolism)
• Peptides (immunology)
• Phosphopyruvate Hydratase (chemistry, immunology, metabolism)
• Phosphorylation
• Protein Interaction Domains and Motifs
• T-Lymphocyte Subsets (immunology, metabolism)
• T-Lymphocytes (immunology, metabolism)
• Tumor Suppressor Proteins (chemistry, immunology, metabolism)