title: 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.affiliation: Centre for Experimental Research and Medical Studies (CERMS), Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Capello
authors.affiliation: Centre for Experimental Research and Medical Studies (CERMS), Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy; Immunogenetic and Transplant Biology Service, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Caorsi
authors.affiliation: Immunogenetic and Transplant Biology Service, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy.
authors.forename: Pablo Josè
authors.initials: PJ
authors.lastname: Bogantes Hernandez
authors.affiliation: Immunogenetic and Transplant Biology Service, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy.
authors.forename: Ennia
authors.initials: E
authors.lastname: Dametto
authors.affiliation: Immunogenetic and Transplant Biology Service, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy.
authors.forename: Francesca Eleonora
authors.initials: FE
authors.lastname: Bertinetto
authors.affiliation: Immunogenetic and Transplant Biology Service, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Magistroni
authors.affiliation: Department of Medical Sciences, Turin University, Turin, Italy.
authors.forename: Sabina
authors.initials: S
authors.lastname: Rendine
authors.affiliation: Immunogenetic and Transplant Biology Service, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy; Department of Medical Sciences, Turin University, Turin, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Amoroso
authors.affiliation: Centre for Experimental Research and Medical Studies (CERMS), Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy; Immunogenetic and Transplant Biology Service, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy; Department of Molecular Biotechnology and Health Sciences, Turin University, Turin, Italy. Electronic address: franco.novelli@unito.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Novelli
mesh_terms: D000483:Alleles; D001323:Autoantibodies / Q000276:immunology*; D014408:Biomarkers, Tumor / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D005787:Gene Frequency; D059810:HLA-DR Serological Subtypes / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D059811:HLA-DRB1 Chains / Q000235:genetics; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D010455:Peptides / Q000276:immunology; D010751:Phosphopyruvate Hydratase / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D010766:Phosphorylation; D054730:Protein Interaction Domains and Motifs; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D059810:HLA-DR Serological Subtypes; C041559:HLA-DR8 antigen; D059811:HLA-DRB1 Chains; D008024:Ligands; D010455:Peptides; D025521:Tumor Suppressor Proteins; C095157:ENO1 protein, human; D010751:Phosphopyruvate Hydratase
keywords: Alpha-enolase (ENOA); Autoantibodies; HLA-DR; Pancreatic cancer