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Open Full Page [CANCER RESEARCH 60, 5522–5528, October 1, 2000] Prostate Stem Cell Antigen Is a Promising Candidate for Immunotherapy of Advanced Prostate Cancer1 Jens Dannull, Pierre-Andre´Diener, Ladislav Prikler, Gregor Fu¨rstenberger, Thomas Cerny, Ulrico Schmid, Daniel K. Ackermann, and Marcus Groettrup2 Departments of Laboratory Research [J. D., M. G.], Urology [L. P., D. K. A.], Oncology [G. F., T. C.], and Pathology [P. A. D., U. S.], Cantonal Hospital St. Gall, 9007 St. Gallen, Switzerland ABSTRACT normal prostate (2–6). However, the identification of target tumor antigens that are capable of overcoming immune tolerance against Immunotherapy of prostate cancer (CaP) may be a promising novel proteins expressed in normal prostate remains a major obstacle for treatment option for the management of advanced CaP. However, the lack developing rational strategies in CaP immunotherapy. Over the past of suitable tumor antigens remains a major obstacle for the rational design of vaccines. To characterize potential CaP antigens, we determined years, several prostate-specific gene products have been reported. the mRNA expression of the prostate-specific genes C1, C2, C5, PAGE-1, These include PSA (7), PSMA (8), PAP (9), prostate carcinoma tumor and prostate stem cell antigen (PSCA) in hormone-refractory CaP, benign antigen 1 (10), PAGE-4 (11), PSP 94 (12), six-transmembrane epi- prostatic hyperplasia, CaP cell lines, and CaP specimens. Among these thelial antigen of the prostate (13), differential display 3 (14), and gene products, only expression of PSCA appears to be retained in the prostate androgen-regulated transcript 1 (15). The rationale of using majority of advanced CaP samples, as shown by reverse transcription- prostate-specific genes as target antigens for immunotherapy is based PCR analyses. Peptide fragments of PSCA presented in the context of on a decade of intensive research in the melanoma field, leading to the major histocompatibility molecules could serve as recognition targets for insight that prominent antigens of melanoma-specific CTLs were CD8 T cells, provided these lymphocytes were not clonally deleted or expressed in melanocytes in a tissue-specific manner (16). Appar- peripherally tolerized. Our goal was to determine whether the human T-cell repertoire could recognize PSCA-derived peptide epitopes in the ently, the presumed tolerance of peripheral T cells against these self context of a common class I allele, HLA-A0201. Of nine peptides that, antigens can be overcome if aberrant expression in tumors occurs. according to HLA-A0201 binding motifs, were candidate ligands of A0201 Moreover, this antitumor response could be successfully enhanced by class I molecules, three peptides were able to stabilize HLA-A0201 mole- several vaccination procedures using melanocyte antigens (17–19). cules on the cell surface. One of the latter peptides, encompassing amino The consequence of this type of antitumor response was on the one acid residues 14–22, was capable of generating a PSCA-specific T-cell hand regression of melanoma lesions but on the other hand vitiligo as response in a human lymphocyte culture from a patient with metastatic a result of CTL-mediated melanocyte destruction. CaP. PSCA-specific CTLs recognized peptide-pulsed targets as well as Because many of the so-called “cancer testis” antigens, which are three prostate carcinoma lines in cytotoxicity assays, indicating that this peptide could be endogenously processed. In conclusion, our findings expressed in testis and in several different malignancies, are not establish PSCA as a potential target for antigen-specific, T cell-based prevalent in the majority of CaP specimens, organ-specific gene immunotherapy of prostate carcinoma. products were considered as target antigens in CaP. This approach seems reasonable because in organ-confined CaP, the prostate is surgically removed and because the life of vaccinated patients would INTRODUCTION not be endangered if healthy prostate tissue was damaged by CTLs. CaP3 is the most common cancer diagnosis and the second leading Unfortunately, the majority of defined prostate-specific gene products cause of cancer-related deaths in men. Despite recent advances in display properties that limit their utilization as antigens in specific detection of CaP and treatment of localized disease, significant chal- immunotherapy of CaP. PSA, PSMA, PAP, PSP 94, and prostate lenges unique to CaP remain to be overcome. In particular, there is no carcinoma tumor antigen 1 are secretory proteins that are found in effective treatment for patients who develop recurrent disease after considerable concentrations in the serum and hence are likely to surgery or radiation therapy or those who have metastatic disease at induce peripheral tolerance. The expression of PSA and PAP in tissue the time of diagnosis. Although hormone ablation therapy may palli- is reduced in neoplastic cells of poorly differentiated tumors com- ate patients with advanced disease temporarily, the progression to pared with normal prostatic tissue and well-differentiated adenocar- incurable hormone-refractory CaP is almost inevitable (1). Therefore, cinomas (20). In addition, PSA has a high degree of homology with the development of novel therapeutic modalities for the treatment of members of the kallikrein family, and PSMA has been found to be hormone-refractory CaP is of paramount importance. Several new expressed in various human tissues (21), thus bearing the risk of CaP treatment approaches aim to eradicate CaP cells by inducing generating autoimmune disease upon protein-based vaccination. PSP systemic immunity to antigens expressed by CaP cells as well as 94 (22) and PAGE-4 (11) seem to be down-regulated in tumor tissue, and expression of six-transmembrane epithelial antigen of the prostate Received 4/28/00; accepted 8/4/00. appears to be expressed at low levels in several other tissues (13). The costs of publication of this article were defrayed in part by the payment of page Prostate androgen-regulated transcript 1 expression is regulated by charges. This article must therefore be hereby marked advertisement in accordance with androgens (15), which is a drawback for strategies aiming to eliminate 18 U.S.C. Section 1734 solely to indicate this fact. 1 This work was supported by Cancer League St. Gallen-Appenzell, Swiss Cancer hormone-refractory tumors. Lastly, the mRNA of differential display League, Foundation Propter Homines, Cancer Research Institute, CaPCURE Foundation, 3 does not contain extensive open reading frames and has, therefore, R. and A. Dietschweiler Foundation, W. and V. Spu¨hl-Foundation, and AstraZeneca AG. 2 To whom requests for reprints should be addressed, at Kantonsspital St. Gallen, been suggested to function as a noncoding RNA (14). Laborforschungsabteilung, Haus 09, CH-9007 St. Gallen, Switzerland. Phone: 44-71-494- However, there are new and partially characterized prostate- 1069; Fax: 44-71-494-6321; E-mail: [email protected]. specific genes that warrant further investigation regarding their po- 3 The abbreviations used are: CaP, carcinoma of prostate; PSA, prostate-specific antigen; PSMA, prostate-specific membrane antigen; PAP, prostatic acid phosphatase; tential as CaP antigens. Little is known about the CaP expression PAGE, prostate antigen encoded gene; PSP, prostate secretory protein; BPH, benign status of C1, C2, and C5, which are prostate-specific mRNAs iden- prostatic hyperplasia; IL, interleukin; PBMC, peripheral blood mononuclear cell; PSCA, prostate stem cell antigen; RT-PCR, reverse transcription-PCR; TAP, transporter associ- tified from expressed sequence tag libraries (23). On the other hand, ated with antigen processing. PAGE-1 (24) and PSCA (25–27) have been identified as gene prod- 5522 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2000 American Association for Cancer Research. PSCA FOR IMMUNOTHERAPY OF PROSTATE CARCINOMA ucts specifically overexpressed in hormone-independent CaP cell T2 Binding Assays. Each peptide was tested for concentration-dependent lines or tumor tissue, respectively. PAGE-1 was identified by differ- binding to T2 cells in HLA-A0201 stabilization assays. T2 (TAP-deficient) ential display PCR as an mRNA that is up-regulated in androgen- cells were incubated at room temperature overnight with the indicated PSCA insensitive metastatic sublines of the CaP cell line LNCaP. The peptides over a range of peptide concentrations from 0.5 to 10 ␮M in the presence of 1 ␮g/ml ␤ -microglobulin (Sigma). Stability of HLA-A0201 was PAGE-1 protein shares 45% homology with antigens of the “cancer- 2 assayed by flow cytometry (FACScan; Becton Dickinson) after staining the testis” family, and its expression was found to be restricted to LNCaP cells with antibody BB7.2 (5 ␮g/ml) and goat antimouse-FITC (AMRAD, sublines, testes, and placenta (24). PSCA was isolated by representa- Melbourne, Australia). The peptide GILGFVFTL of influenza matrix protein, tional difference analysis in the LAPC-4 xenograft model and was residues 58–66, was used as a positive control. Alternatively, in “off-assays,” found to be up-regulated in tumor xenografts when compared with T2 cells were incubated overnight at room temperature in the presence of 10 Ϫ normal prostate (25). The PSCA gene codes for a 123-amino acid ␮M peptide, followed by an incubation at 37°C in the presence of 10 4 M glycoprotein that is not homologous to other genes except for a 30% emetine (Sigma). The loss of HLA-A0201 molecules from the cell surface was
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