Identification of a Novel Tumor-Associated Antigen, Cadherin 3/P-Cadherin, as a Possible Target for Immunotherapy of Pancreatic, Gastric, and Colorectal Cancers

Abstract

Purpose: To establish cancer immunotherapy, it is important to identify the tumor-associated antigens (TAA) that are strongly expressed in the tumor cells but not in the normal cells. In this study, to establish an effective anticancer immunotherapy, we tried to identify the useful TAA of pancreatic cancer. Experimental Design: Based on a previous genome-wide cDNA microarray analysis of pancreatic cancer, we focused on cadherin 3 (CDH3)/P-cadherin as a novel candidateTAA for anticancer immunotherapy. To identify the HLA-A2 (A*0201)^restricted CTL epitopes of CDH3, we used HLA-A2.1 (HHD) transgenic mice (Tgm). Furthermore, we examined the cytotoxicity against the tumor cells in vitro and in vivo of CTLs specific to CDH3 induced from HLA-A2p ositive healthy donors and cancer patients. Results: CDH3 was overexpressed in the majority of pancreatic cancer and various other malignancies, including gastric and colorectal cancers, but not in their noncancerous counterparts or in many normal adult tissues. In the experiment using HLA-A2.1 Tgm, we found that the CDH3-4 655-663 (FILPVLGAV) and CDH3-7 757-765 (FIIENLKAA) peptides could induce HLA-A2^restricted CTLs inTgm. In addition, peptides-reactive CTLs were successfully induced from peripheral blood mononuclear cells by in vitro stimulation with these two peptides in HLAA2^positive healthy donors and cancer patients, and these CTLs exhibited cytotoxicity specific to cancer cells expressing both CDH3 and HLA-A2. Furthermore, the adoptive transfer of the CDH3-specific CTLs could inhibit the tumor growth of human cancer cells engrafted into nonobese diabetic/severe combined immunodeficiency mice. Conclusions: These results suggest that CDH3 is a novel TAA useful for immunotherapy against a broad spectrum of cancers, including pancreatic cancer.Pancreatic cancer has a poor prognosis, with an overall 5-year survival rate of f5% (1). A surgical resection remains the only option for a long-term survival, but patients with resectable pancreatic cancer are in the minority (9-22%; refs. 2 -4). Even in these patients, however, the 5-year survival rate remains f20% in spite of surgery with a curative intent (5, 6). Up to 80% of patients present with locally advanced or metastatic disease, and their median survival ranges from 6 to 9 months (7). It is generally thought that the presence of few signs or symptoms in the early stage, lack of an effective screening test, high rate of relapse, and poor response to current therapies contribute to the poor prognosis of this malignancy. Hence, the development of novel therapeutic modalities is an issue of great importance, and immunotherapy may be a potential treatment for pancreatic cancer.To establish an effective antitumor immunotherapy, the identification of tumor-associated antigens (TAA) plays a key role. In the past, many TAAs in various malignancies have been identified using the method of cDNA expression cloning (8 -10) and a serologic analysis of the recombinant cDNA expression library (11 -15). Recently, cDNA microarray...

P-cadherin expression as a prognostic biomarker in a 3992 case tissue microarray series of breast cancer

“…85 P-cadherin has been suggested as a possible target for immunotherapy of pancreatic, gastric, and colorectal cancers based on the identification of HLA-A2-restricted cytotoxic T lymphocyte epitopes of P-cadherin in HLA-A2.1 transgenic mice, and the in vitro and in vivo cytotoxicity against tumor cells of cytotoxic T lymphocyte specific to CDH3 induced from HLA-A2-positive healthy donors and cancer patients. 86 In conclusion, this study shows the value of P-cadherin expression as a marker of poor prognosis in a large breast cancer series. P-cadherin positivity is associated with high-grade tumor subtypes (HER2 þ and basal carcinomas), and well-established markers of poor prognosis (ER, PR, Bcl-2), and may represent a promising antibody therapeutic target, either by exploiting its association with poor prognosis tumor, or by modulating its role in cell adhesion and migration.…”

P-cadherin role in normal breast development and cancer

“…Interestingly, in 2008, Imai and collaborators have suggested CDH3/P-cadherin as a possible target for immunotherapy of pancreatic, gastric, and colorectal cancers, since it was identified as a novel tumour-associated antigen, meaning that was strongly expressed in tumour cells, but not in normal cells (Imai et al, 2008). Indeed, we have found that P-cadherin silencing, in breast cancer cells inoculated in nude mice, was able to significantly inhibit in vivo tumour growth (unpublished data).…”

“…P-cadherin upregulation was frequently observed in various malignant tumours, including breast, gastric, endometrial, colorectal and pancreatic carcinomas, and is correlated with poor survival of breast cancer patients (Hardy et al, 2002, Imai et al, 2008, Stefansson et al, 2004, Taniuchi et al, 2005. In contrast, significantly low levels of the P-cadherin gene expression were detected in a diverse panel of normal tissues (Imai et al, 2008). Thus, disruption of P-cadherin signalling represents an intriguing opportunity for the development of novel targeted therapeutic agents in cancer.…”

PF-03732010: A Fully Human Monoclonal Antibody against P-Cadherin with Antitumor and Antimetastatic Activity

“…The upregulation of P-cadherin was frequently observed in various malignant tumors, including breast, colon, lung, and pancreatic tumors, and correlated with poor survival of breast cancer patients (15,20,21). In contrast, significantly low levels of the P-cadherin gene expression were detected in a diverse panel of normal tissues (22). Thus, disruption of P-cadherin signaling represents an intriguing opportunity for the development of novel targeted therapeutic agents.…”