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 Serine419phosphorylated ENOA (Ser419P-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 Ser419, 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 Ser419P-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 Ser419P-ENOA peptide with the HLA that trigger T-cell signaling might be relevant for induction of anti-tumor immune response.

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

CAPELLO, Michela;CAORSI, Cristiana;BERTINETTO, FRANCESCA;RENDINE, Sabina;AMOROSO, Antonio;NOVELLI, Francesco
2015

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 Serine419phosphorylated ENOA (Ser419P-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 Ser419, 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 Ser419P-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 Ser419P-ENOA peptide with the HLA that trigger T-cell signaling might be relevant for induction of anti-tumor immune response.
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http://www.sciencedirect.com/science/article/pii/S0165247815001145
Pancreatic cancer, Alpha-enolase (ENOA), Autoantibodies, HLA-DR.
Capello, M; Caorsi, C; Bogantes Hernandez, Pj; Dametto, E; Bertinetto, Fe; Magistroni, P; Rendine, S; Amoroso, A; Novelli, F
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1529359
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