An integrated humoral and cellular response is elicited in pancreatic cancer by α‐enolase, a novel pancreatic ductal adenocarcinoma‐associated antigen

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with a very poor 5-year survival rate. a-Enolase is a glycolytic enzyme that also acts as a surface plasminogen receptor. We find that it is overexpressed in PDAC and present on the cell surface of PDAC cell lines. The clinical correlation of its expression with tumor status has been reported for lung and hepatocellular carcinoma. We have previously demonstrated that sera from PDAC patients contain IgG autoantibodies to a-enolase. The present work was intended to assess the ability of a-enolase to induce antigen-specific T cell responses. We show that a-enolase-pulsed dendritic cells (DC) specifically stimulate healthy autologous T cells to proliferate, secrete IFN-c and lyse PDAC cells but not normal cells. In vivo, a-enolase-specific T cells inhibited the growth of PDAC cells in immunodeficient mice. In 8 out of 12 PDAC patients with circulating IgG to a-enolase, the existence of a-enolase-specific T cells was also demonstrated. Taken as a whole, these results indicate that a-enolase elicits a PDAC-specific, integrated humoral and cellular response. It is thus a promising and clinically relevant molecular target candidate for immunotherapeutic approaches as new adjuvants to conventional treatments in pancreatic cancer. ' 2009 UICC

Vaccination With ENO1 DNA Prolongs Survival of Genetically Engineered Mice With Pancreatic Cancer

“…5 Sera collected 2 weeks after 3 rounds of vaccination were diluted 1:500 in phosphate-buffered saline (PBS) and antibody concentration was calculated by regression analysis using 8 two-fold serial dilutions of 1 g/mL of 72/1.11 monoclonal antibody (mAb) for a standard curve (kindly provided by P. Migliorini, University of Pisa, Pisa, Italy).…”

“…4 ENO1 is coded by the ENO1 gene, is overexpressed in the cytoplasm of PDA cells, and is also present on their membrane. 5 In the cytoplasm, ENO1 acts as a glycolytic enzyme, whereas on the membrane it acts as a plasminogen receptor and plays an important role in cell migration. 6,7 We have shown that patients with PDA with autoantibodies to ENO1 also present an ENO1-specific T-cell response that is not observed in patients with no ENO1 autoantibodies.…”

“…Despite the ubiquitous presence of ENO1 in all mammalian cells, normal cells expressing low levels of ENO1 are spared by ENO1-specific cytotoxic T lymphocytes. 5 In this work, we used 2 genetically engineered mice strains (Kras G12D /Cre mice [KC mice] and Kras G12D / Trp53 R172H /Cre mice [KPC mice]) that develop autochthonous lethal pancreatic carcinomas with different kinet-ics 8,9 to study the protective effect of a DNA vaccine to human ENO1.…”

Glucose Metabolism and Cancer

“…In pancreatic cancer patients, the anti-ENOA autoantibodies are directed against phosphorylated Serine 419 (Tomaino et al, 2011). One study has shown that, in pancreatic cancer, ENOA elicits a CD4+ and CD8+ T cell response both in vitro and in vivo (Cappello et al, 2009). In pancreatic cancer patients, production of anti-ENOA IgG is correlated with the ability of T cells to be activated in response to ENOA (Cappello et al, 2009).…”

“…One study has shown that, in pancreatic cancer, ENOA elicits a CD4+ and CD8+ T cell response both in vitro and in vivo (Cappello et al, 2009). In pancreatic cancer patients, production of anti-ENOA IgG is correlated with the ability of T cells to be activated in response to ENOA (Cappello et al, 2009). In patients with oral squamous cell carcinoma, an HLA-DR8-restricted peptide (amino acid residues 321-336) of human ENOA recognized by CD4+ T cell has been identified (Kondo et al, 2002).…”