Abstract
BackgroundProstate cancer is the most common cancer among elderly men in the US, and immunotherapy has been shown to be a promising strategy to treat patients with metastatic castration-resistant prostate cancer. Efforts to identify novel prostate specific tumor antigens will facilitate the development of effective cancer vaccines against prostate cancer. Prostate-specific G-protein coupled receptor (PSGR) is a novel antigen that has been shown to be specifically over-expressed in human prostate cancer tissues. In this study, we describe the identification of PSGR-derived peptide epitopes recognized by CD8+ T cells in an HLA-A2 dependent manner.Methodology/Principal FindingsTwenty-one PSGR-derived peptides were predicted by an immuno-informatics approach based on the HLA-A2 binding motif. These peptides were examined for their ability to induce peptide-specific T cell responses in peripheral blood mononuclear cells (PBMCs) obtained from either HLA-A2+ healthy donors or HLA-A2+ prostate cancer patients. The recognition of HLA-A2 positive and PSGR expressing LNCaP cells was also tested. Among the 21 PSGR-derived peptides, three peptides, PSGR3, PSGR4 and PSGR14 frequently induced peptide-specific T cell responses in PBMCs from both healthy donors and prostate cancer patients. Importantly, these peptide-specific T cells recognized and killed LNCaP prostate cancer cells in an HLA class I-restricted manner.Conclusions/SignificanceWe have identified three novel HLA-A2-restricted PSGR-derived peptides recognized by CD8+ T cells, which, in turn, recognize HLA-A2+ and PSGR+ tumor cells. The PSGR-derived peptides identified may be used as diagnostic markers as well as immune targets for development of anticancer vaccines.
Highlights
Prostate cancer has become the most common cancer among men in the US and is the second leading cause of death from cancer in American men [1]
All protocols were approved by the Institutional Review Board (IRB) of Baylor College of Medicine before commencing studies. 20 mL of peripheral blood was obtained from each person, and peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation using Lymphoprep (Nycomed Pharma AS; Oslo, Norway)
To determine whether PSGR-reactive T cell precursors are present in healthy subjects, we obtained PBMCs from 10 HLAA2+ healthy donors and stimulated them in vitro with each of the 21 PSGR-derived peptides containing HLA-A2-binding motif (Table 1)
Summary
Prostate cancer has become the most common cancer among men in the US and is the second leading cause of death from cancer in American men [1]. Androgen-deprivation therapy is an effective treatment against recurrent disease, most of these patients eventually develop androgen-refractory prostate cancer, which is insensitive to traditional treatment. Immunotherapy has been shown to be a promising approach to the treatment of prostate cancer, especially for patients with metastatic castration-resistant prostate cancer [2,3,4]. A recent study using animal models further reveals the importance of tumor-specific antigens in eliciting immune responses against a developing tumor [10], spurring more efforts to identify such antigens for cancer immunotherapy. Prostate cancer is the most common cancer among elderly men in the US, and immunotherapy has been shown to be a promising strategy to treat patients with metastatic castration-resistant prostate cancer. Efforts to identify novel prostate specific tumor antigens will facilitate the development of effective cancer vaccines against prostate cancer. We describe the identification of PSGR-derived peptide epitopes recognized by CD8+ T cells in an HLA-A2 dependent manner
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