MAGE-A p248V9 – YLEYRQVPV – Epitope of Melanoma Antigen Gene
MAGE-A protein
MAGE-A p248V9, also kwon as multi-MAGE-A (YLEYRQVPV) is an epitope of Melanoma Antigen Gene expressed by tumors of different histological types and is a Cancer/Testis Antigens (CTA). Type of MAGE-A expressed in tumors cells varies according to the type of tumor. Targeting epitopes shared by all MAGE-A antigens would be interest in immunotherapy against a broad spectrum of cancers.
Applications of MAGE-A p248V9 (multi-MAGE-A)
MAGE-A p248V9 is very useful because it could generate an HLA-A*02:01-restricted CTL response and shared by MAGE-A1,-A2,-A3,-A4,-A6,-A10 and -A12. MAGE-A p248V9 is used to stimulate specific cytotoxic T lymphocytes (CTL) in PBMCs and then to analyze CTL response especially the cytokine production by ELISPOT assay.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. Tumor specific cellular and humoral immunotherapy may be a viable approach for the treatment of HCC. This study investigated specific inhibitory and cytotoxic effects on hepatocellular carcinoma (HCC) induced by the peptide, designated HBcΔ-5L, using HBc carrier with multiple T cell and B cell sequence insertions. We developed the HBcΔ carrier containing insertions of multiple CTL and T helper (Th) epitopes, which were selected from HCC tumor associated antigens (TAAs) including α fetoprotein (AFP), melanoma antigen gene (MAGE) and telomerase reverse transcriptase (TERT) antigen, and ligands for EGFR and IGFR, designated HBcΔ-5L. LDH release assay and IFN-γ ELISPOT assay were carried to determine whether HBcΔ-5L could induce specific cytotoxicity in peripheral blood mononuclear cells (PBMC) of HCC donors. The levels of antibodies and inhibitory effects of sera of immunized mice against HBcΔ-5L were also identified. LDH release assay revealed that PBMC from HCC donor group (n=8) stimulated with HBcΔ-5L could specifically kill target tumor cells and specific lysis was 62.7% (E:T=60:1). ELISPOT assay showed a significant increase in secretion of IFN-γ from PBMC of HCC donor group in response to HBcΔ-5L. Further, high specific antibody titers were elicited in immunized mice and revealed 42% inhibition of cell growth. These results indicated that inhibitory and cytotoxic effects could be efficiently induced by HBcΔ-5L recombinant particles using HBcΔ as carrier and suggested that it could be important in design of immunotherapeutic approaches.
2- Lurquin C. et al. J Exp Med. 201(2):249-257 (2005)
Melanoma patients have high frequencies of T cells directed against antigens of their tumor. The frequency of these antitumor T cells in the blood is usually well above that of the anti-vaccine T cells observed after vaccination with tumor antigens. In a patient vaccinated with a MAGE-3 antigen presented by HLA-A1, we measured the frequencies of anti-vaccine and antitumor T cells in several metastases to evaluate their respective potential contribution to tumor rejection. The frequency of anti-MAGE-3.A1 T cells was 1.5 x 10(-5) of CD8 T cells in an invaded lymph node, sixfold higher than in the blood. An antitumor cytotoxic T lymphocyte (CTL) recognizing a MAGE-C2 antigen showed a much higher enrichment with a frequency of approximately 10%, 1,000 times higher than its blood frequency. Several other antitumor T clonotypes had frequencies >1%. Similar findings were made on a regressing cutaneous metastasis. Thus, antitumor T cells were approximately 10,000 times more frequent than anti-vaccine T cells inside metastases, representing the majority of T cells present there. This suggests that the anti-vaccine CTLs are not the effectors that kill the bulk of the tumor cells, but that their interaction with the tumor generates conditions enabling the stimulation of large numbers of antitumor CTLs that proceed to destroy the tumor cells. Naive T cells appear to be stimulated in the course of this process as new antitumor clonotypes arise after vaccination.
3- Graff-Dubois S. Faure O., Gross D-A., Alves P, Scardino A., Chouaib S., Lemonnier F. A. and Kosmatopoulos K. J. Immunol. 169(1):575-580 (2002)
MAGE-A1, -A2, -A3, -A4, -A6, -A10, and -A12 are expressed in a significant proportion of primary and metastatic tumors of various histological types and are targets of tumor Ag-specific CTL. Individual MAGE-A expression varies from one tumor type to the other but, overall, the large majority of tumors expresses at least one MAGE-A Ag. Therefore, targeting epitopes shared by all MAGE-A Ags would be of interest in immunotherapy against a broad spectrum of cancers. In the present study, we describe a heteroclitic MAGE-A peptide (p248V9) that induces CTL in vivo in HLA-A*0201 transgenic HHD mice and in vitro in healthy donors. These CTL are able to recognize two low HLA-A*0201 affinity peptides differing at their C-terminal position and derived from MAGE-A2, -A3, -A4, -A6, -A10, and -A12 (p248G9) and MAGE-A1 (p248D9). Interestingly, p248V9-specific CTL respond to endogenous MAGE-A1, -A2, -A3, -A4, -A6, -A10, and -A12 in an HLA-A*0201-restricted manner and recognize human HLA-A*0201+MAGE-A+ tumor cells of various histological origin. Therefore, this heteroclitic peptide may be considered as a potent candidate for a broad-spectrum tumor vaccination.
4- Chomez P., De Backer O., Bertrand M., De Plaen E., Boon T. and Lucas S. Cancer Res. 61(14):5544-5551 (2001)
The first human members of the MAGE gene family that have been described are expressed in tumor cells but silent in normal adult tissues except in the male germ line. Hence, they encode strictly tumor-specific antigens that represent attractive targets for cancer immunotherapy. However, other members of the family were recently found to be expressed in normal cells, indicating that the family is larger and more disparate than initially expected. We therefore performed a database screening to identify all of the recorded members of both classes of human MAGE genes. This report provides an overview of the MAGE family and proposes a general nomenclature for all of the MAGE genes identified thus far. We found that the MAGE-D genes were particularly well conserved between man and mouse, suggesting that they exert important functions. In addition, the genomic structure of the MAGE-D genes indicates that one of them corresponds to the founder member of the family, and that all of the other MAGE genes are retrogenes derived from that common ancestral gene. Intriguingly, the COOH-terminal domain of MAGE-D3 was found to be identical to trophinin, a previously described protein believed to be involved in embryo implantation.
5- Groeper C. et al. Int J Cancer. 120(2):337-343 (2007)
Non small cell lung cancers (NSCLC) express cancer/testis antigens (CTA) genes and MAGE-A expression correlates with poor prognosis in squamous cell carcinomas. We addressed cytotoxic T lymphocytes (CTL) responses to HLA class I restricted CTA epitopes in TIL from NSCLC in an unselected group of 33 patients consecutively undergoing surgery. Expression of MAGE-A1, -A2, -A3, -A4, -A10, -A12 and NY-ESO-1 CTA genes was tested by quantitative RT-PCR. Monoclonal antibodies (MAb) recognizing MAGE-A and NY-ESO-1 CTA were used to detect CTA by immunohistochemistry. CD8(+) TIL obtained from tumors upon culture with anti CD3 and anti CD28 mAb and IL-2 were stimulated with autologous mature DC (mDC) and HLA-A*0101 restricted MAGE-A1(161-169) or MAGE-A3(168-176) peptides or HLA-A*0201 restricted MAGE-A4(230-239), MAGE-A10(254-262), NY-ESO-1(157-165) or multi-MAGE-A (YLEYRQVPV) peptides or a recombinant vaccinia virus (rVV) encoding MAGE-A and NY-ESO-1 HLA-A*0201 restricted epitopes and CD80 co-stimulatory molecule. Specificity was assessed by (51)Cr release and multimer staining. At least one CTA gene was expressed in tumors from 15/33 patients. In 10 specimens, at least 4 CTA genes were concomitantly expressed. These data were largely confirmed by immunohistochemistry. TIL were expanded from 26/33 specimens and CTA-specific CTL activity was detectable in 7/26 TIL. In 6, however, specific cytotoxicity was weak, (<40% lysis at a 50:1 E:T ratio) and multimer staining was undetectable. In one case, high (>60% lysis at 50:1 E:T ratio) MAGE-A10(254-262) specific, HLA-A*0201 restricted response was observed. Supportive evidence was provided by corresponding multimer staining. Although CTA genes are frequently expressed in NSCLC, detection of CTL reactivity against CTA epitopes in TIL from nonimmunized NSCLC patients represents a rare event.
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