The HER2/neu‐derived peptide p654–662 is a tumor‐associated antigen in human pancreatic cancer recognized by cytotoxic T lymphocytes

Abstract

The protooncogene HER2/neu encodes a 185-kDa transmembrane protein with extensive homology to the epidermal growth factor receptor. It is overexpressed in several human cancers of epithelial origin, such as pancreatic cancer. Previously, we demonstrated that cytotoxic T lymphocytes (CTL) derived from breast, ovarian, and non-small cell lung cancer recognized a peptide derived from HER2/neu. To evaluate whether this HLA-A2-binding peptide is a tumor-associated antigen (TAA) in pancreatic cancer, the ability of HER2/neu-reactive CTL to lyse human pancreatic carcinoma cells was tested. CTL were generated from tumor-associated T lymphocytes from HLA-A2+ HER2/neu+ breast and ovarian cancer patients. All CTL recognized autologous and allogeneic HER2/ neu+ tumor cells in an HLA-A2-restricted fashion. Furthermore, all CTL recognized p654-662 (GP2) derived from HER2/neu. These CTL also recognized HER2/neu+ pancreatic cancer cells in an HLA-A2-restricted fashion. HER2/neu+ HLA-A2- pancreatic cancer were not or only poorly lysed. Repeated stimulation of HLA-A2+ PBL from pancreatic cancer patients using the HER2/neu-derived peptide resulted in specific recognition of this peptide and, more importantly, HER2/neu+ pancreatic tumors in an HLA-A2-restricted fashion. Autologous HLA-A2+ fibroblasts or HLA-A2+ malignant melanoma cells were not recognized. HLA-A2- peptide-stimulated T lymphocytes showed no significant cytotoxicity. These results demonstrate that this HER2/neu-derived peptide is a shared TAA among several adenocarcinomas including pancreatic carcinoma, suggesting a common mechanism of recognition of these human tumors by T lymphocytes. The identification of the HER2/neu-derived peptide GP2 as a TAA in pancreatic cancer provides an opportunity for the design of novel immunotherapy and vaccine strategies.

Results of the first phase 1 clinical trial of the HER‐2/neu peptide (GP2) vaccine in disease‐free breast cancer patients

“…7 The peptide was isolated using tumor-associated lymphocytes from patients with breast and ovarian cancer, and later found to be shared among several epithelial malignancies including nonsmall cell lung cancer and pancreatic cancer. [15][16][17][18] GP2 differs from E75 in that it has been termed a subdominant epitope of the HER-2/neu protein because of its relatively lower binding affinity for the HLA-A2 molecule. 7,19 E75, conversely, has a high affinity for HLA-A2 and has been identified as the immunodominant HER-2/neu epitope.…”

Immune responses to DNA mismatch repair enzymes hMSH2 and hPMS1 in patients with pancreatic cancer, dermatomyositis and polymyositis

“…However, the mechanism for immunological tumor regression has not been well evaluated and improvement of the immunotherapy has been difficult partly because only a limited number of tumor antigens have so far been identified for pancreatic cancer. 16,17 Furthermore, additional tumor markers are required for better diagnosis of pancreatic cancer. Thus, identification of additional antigens is important for development of immunotherapy and diagnostic methods for patients with pancreatic cancer.…”

Redirecting mouse T hybridoma against human breast and ovarian carcinomas: in vivo activity against HER-2/neu expressing cancer cells

“…Thus, CTL responses specific for MHC class I HER-2/neu epitopes have been observed in some patients with cancer and HER-2/neu-specific IgG antibodies have been detected in the sera of patients with HER-2/neu + cancers (Disis et al, 1994a, b;Yoshino et al, 1994;Knutson et al, 2001). Furthermore, tumour-reactive CTL-and helper T-cell responses could be induced in vitro using various recently identified MHC class I-or class II-binding peptides (Peiper et al, 1997;Brossart et al, 1998;Kobayashi et al, 2000;Sotiriadou et al, 2001;Baxevanis et al, 2002;Perez et al, 2002). Adoptive cellular immunotherapy utilizing patients' T lymphocytes primed in vitro to recognise HER-2/neu epitopes represents one major modality for treating patients carring HER-2/ neu + tumours.…”

“…HER-2/neu is ubiquitously expressed in many epithelial tumours and known to be overexpressed in approximately 30% of all ovarian and breast cancers (Slamon et al, 1989(Slamon et al, , 2001, 35 -45% of all pancreatic carcinomas (Yamanaka et al, 1993) and up to 90% of colorectal carcinomas (Maxwell-Armstrong et al, 1998) and this overexpression was shown to correlate with aggressiveness of malignancy and poor prognosis (Slamon et al, 1989;Pauletti et al, 1996). The HER-2/neu protein appears to be immunogenic because T-lymphocyte responses to both MHC class I-and class II-restricted epitopes have been observed (Yoshino et al, 1994;Fisk et al, 1995;Peiper et al, 1997;Brossart et al, 1998;Rongcun et al, 1999;Sotiriadou et al, 2001;Baxevanis et al, 2002;Perez et al, 2002). However, the use of such peptide epitopes for vaccination studies is limited to only those patients who express the appropriate MHC class I and class II alleles.…”