MAGE-A8 overexpression in transitional cell carcinoma of the bladder: identification of two tumour-associated antigen peptides

Bar-Haim, Erez; Paz, Adrian; Machlenkin, Arthur; Hazzan, David; Tirosh, Boaz; Carmon, Lior; Brenner, Baruch; Vadai, Ezra; Mor, Orna; Stein, Avi; Lemonnier, François; Tzehoval, Esther; Eisenbach, Lea

doi:10.1038/sj.bjc.6601968

Cited by 19 publications

(12 citation statements)

References 32 publications

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“…The HHD mouse combines classic HLA transgenesis (HLA-A2.1/D b -h2m single chain) with selective destruction of murine H-2 (double knockout deletion of the murine h2m and D b genes) that restricts the whole class I-derived T-cell repertoire to HLA-A2.1. Others and we have identified several HLA-A2.1-restricted epitopes from TAAs, such as MUC1 (21), BA46 (22), PTH-rP (30), HER-2/neu and hTERT (31), and MAGE-A8 (32). PAP, PSA, PSMA, and STEAP were found to be overexpressed in prostate cancer versus BPH samples (Fig.…”

Section: Discussionmentioning

confidence: 99%

Human CTL Epitopes Prostatic Acid Phosphatase-3 and Six-Transmembrane Epithelial Antigen of Prostate-3 as Candidates for Prostate Cancer Immunotherapy

et al. 2005

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Specific immunotherapy of prostate cancer may be an alternative or be complementary to other approaches for treatment of recurrent or metastasized disease. This study aims at identifying and characterizing prostate cancerassociated peptides capable of eliciting specific CTL responses in vivo. Evaluation of peptide-induced CTL activity in vitro was done following immunization of HLA-A2 transgenic (HHD) mice. An in vivo tumor rejection was tested by adoptive transfer of HHD immune lymphocytes to nude mice bearing human tumors. To confirm the existence of peptide-specific CTL precursors in human, lymphocytes from healthy and prostate cancer individuals were stimulated in vitro in the presence of these peptides and CTL activities were assayed. Two novel immunogenic peptides derived from overexpressed prostate antigens, prostatic acid phosphatase (PAP) and sixtransmembrane epithelial antigen of prostate (STEAP), were identified; these peptides were designated PAP-3 and STEAP-3. Peptide-specific CTLs lysed HLA-A2.1 + LNCaP cells and inhibited tumor growth on adoptive immunotherapy. Furthermore, peptide-primed human lymphocytes derived from healthy and prostate cancer individuals lysed peptide-pulsed T2 cells and HLA-A2.1 + LNCaP cells. Based on the results presented herein, PAP-3 and STEAP-3 are naturally processed CTL epitopes possessing anti-prostate cancer reactivity in vivo and therefore may constitute vaccine candidates to be investigated in clinical trials. (Cancer Res 2005; 65(14): 6435-42)

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Section: Discussionmentioning

confidence: 99%

Human CTL Epitopes Prostatic Acid Phosphatase-3 and Six-Transmembrane Epithelial Antigen of Prostate-3 as Candidates for Prostate Cancer Immunotherapy

et al. 2005

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“…Antigens that are uniquely expressed in tumours (Luftl et al, 2004); antigens derived from differentiation markers (Panelli et al, 2000); antigens arise from mutations that are common in tumours (McArdle et al, 2000); antigens from a viral source (Youde et al, 2004); and selfantigens that are overexpressed in tumours (Bar-Haim et al, 2004). In the latter category, although strong immune reactions against this type of antigens might result in the destruction of normal tissues, experience with peptide immunisation has not demonstrated high toxicity in humans and animals (Gross et al, 2004).…”

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confidence: 99%

‘1-8 interferon inducible gene family’: putative colon carcinoma-associated antigens

et al. 2007

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D bÀ/À xb2 microglobulin (b2m) null mice transgenic for a chimeric HLA-A2.1/D b -b2m single chain (HHD mice) are an effective biological tool to evaluate the antitumour cytotoxic T-lymphocyte response of known major histocompatibility-restricted peptide tumour-associated antigens, and to screen for putative unknown novel peptides. We utilised HHD lymphocytes to identify immunodominant epitopes of colon carcinoma overexpressed genes. We screened with HHD-derived lymphocytes over 500 HLA-A2.1-restricted peptides derived from colon carcinoma overexpressed genes. This procedure culminated in the identification of seven immunogenic peptides, three of these were derived from the 'human 1-8D gene from interferon inducible gene' (1-8D). The 1-8D gene was shown to be overexpressed in fresh tumour samples. The three 1-8D peptides were both antigenic and immunogenic in the HHD mice. The peptides induce cytotoxic T lymphocytes that were able to kill a colon carcinoma cell line HCT/HHD, in vitro and retard its growth in vivo. One of the peptides shared by all the 1-8 gene family primed efficiently normal human cytotoxic T lymphocyte precursors. These results highlight the 1-8D gene and its homologues as putative immunodominant tumour-associated antigens of colon carcinoma.

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“…8 More recently, Bar-Haim et al reported the overexpression of MAGE-A8 mRNA in 70% of bladder tumours. 9 In our previous analysis, 7 we observed that only half of tumours expressing MAGE-A mRNAs were positive on Western blot with mAb 57B, a mAb that cross reacts with MAGE-A1, -A2, -A3, -A4, -A6 and -A12 antigens. 10,11 We made a similar observation using the bladder cancer cell line RT4, which strongly expressed MAGE-A transcripts but was negative with mAb 57B.…”

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MAGE‐A9 mRNA and protein expression in bladder cancer

Picard

Bergeron

LaRue

et al. 2007

Intl Journal of Cancer

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In a previous analysis, we showed that MAGE-As were the most frequently expressed cancer-testis antigens in human bladder tumours. Here, we further characterized by RT-PCR the expression of this family of genes by analyzing specifically MAGE-A3, -A4, -A8 and -A9 mRNAs in 46 bladder tumours and 10 normal urothelia. We found that they were expressed in 30, 33, 56 and 54% of tumours, respectively. Although MAGE-A8 was the most frequent, its expression was low and was also found in most normal urothelia. The other MAGE-A mRNAs were all tumour-specific but MAGE-A9 mRNA was expressed at a higher level and was two times more frequent in superficial than in invasive tumours. To study the expression of the protein, we produced 2 MAGE-A9-specific monoclonal antibodies (mAbs) presenting no cross-reactivity with other MAGE-A proteins. MAb 14A11, was used to analyse the expression of the antigen in testis and tumour samples by immunohistochemistry. In testis, MAGE-A9 expression was restricted to primary spermatocytes. Most bladder tumours that expressed the MAGE-A9 transcript were positive with mAb 14A11. Staining was heterogeneous but half of the tumours showed over 75% positive cells. Finally, we showed that treatment of bladder cancer cells with the methylation inhibitor, 5-aza-2 0 -deoxycytidine, alone or in combination with the histone deacetylase inhibitors MS-275 and 4-phenylbutyrate could strongly induce the expression of MAGE-A9. These results show that MAGE-A9 is frequently expressed in superficial bladder cancer and could be a relevant target for immunotherapy or chemoimmunotherapy because its expression can be induced by chemotherapeutic drugs. ' 2007 Wiley-Liss, Inc.Key words: bladder cancer; cancer-testis antigens; MAGE-A9; immunotherapy; DNA methylation Bladder cancer is the fifth most common cancer in the Western world. Most of these tumours are transitional cell carcinomas and about 75% are superficial. 1 Although most of these tumours present a good prognosis, they are associated with a high rate of recurrence since more than 60% will recur after surgery, and a significant proportion of these recurrences (5-25%) will be progression toward a more aggressive disease. Superficial bladder cancer thus represents a unique opportunity to develop and test cancer vaccines that could be used after surgery to prevent tumour recurrence, in an ideal setting of low tumour burden. Moreover, we hypothesize that this type of cancer could respond well to specific immunotherapy because it is one of the rare cancers to show clinical response after intravesical instillation of bacillus CalmetteGuerin, a nonspecific immunotherapy treatment. 1 Cancer-testis antigens (CTAs) possess several features of ideal targets for cancer immunotherapy. They are expressed in a large variety of tumours but their expression in normal tissues is restricted to gametogenic tissues, which are immunopriviledged because of their lack or low expression of HLA molecules. [2][3][4] Moreover, several studies have shown the existence of natural cellular an...

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MAGE-A8 overexpression in transitional cell carcinoma of the bladder: identification of two tumour-associated antigen peptides

Cited by 19 publications

References 32 publications

Human CTL Epitopes Prostatic Acid Phosphatase-3 and Six-Transmembrane Epithelial Antigen of Prostate-3 as Candidates for Prostate Cancer Immunotherapy

Human CTL Epitopes Prostatic Acid Phosphatase-3 and Six-Transmembrane Epithelial Antigen of Prostate-3 as Candidates for Prostate Cancer Immunotherapy

‘1-8 interferon inducible gene family’: putative colon carcinoma-associated antigens

MAGE‐A9 mRNA and protein expression in bladder cancer

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