MAGE-A1 (278-286) is an epitope of Melanoma Antigen Gene A1 expressed by tumors of different histological types such as on the surface of breast carcinoma cell and is a Cancer/Testis Antigens (CTA). MAGE-A1 is a tumor antigen expressed in 40% of melanoma and contains epitope for binding HLA-A*02:01 molecules and that are recognized by cytotoxic T cells.
Applications of MAGE-A1 (278-286)
MAGE-A1 (278-286) is used to stimulate specific cytotoxic T cells in PBMCs and to analyze by ELISPOT peptide epitope specificity and cytokine production like IFN-γ. Immunogenicity of MAGE-A1 (278-286) raised the possibility of developing anticancer immunotherapies or vaccinations. MAGE-A1 is also expressed in lung adenocarcinoma and studies suggest that MAGE-A1 may serve to develop Chimeric Antigen Receptor (CAR) T cell therapy using lentiviral vector and show an encouraging tumor-inhibitory efficacy.
Peptides presented by HLA-A*0201 molecules on the surface of the human breast carcinoma cell line KS24.22 after IFN-γ induction were analyzed by the “Predict-Calibrate-Detect” approach,which combines epitope prediction and high-performance liquid chromatography mass spectrometry. One of the predicted epitopes,MAGE-A1278–286 (KVLEYVIKV),was found to be presented by HLA-A*0201,with an estimated copy number of 18 molecules/cell. HLA-A*0201 transgenic mice (HHD mice) were used to generate CTL lines that stained positive with an HLA-A*0201 tetramer folded around the KVLEYVIKV peptide and killed peptide-loaded mouse target cells expressing HLA-A*0201. IFN-γ-treated or -nontreated HLA-A*0201 expressing HeLa cells transiently transfected with a plasmid expressing the MAGE-A1 gene stimulated in vitro cytokine production by the CTL lines. Moreover,IFN-γ-treated KS24.22 cells,but not IFN-γ-treated HLA-A*0201+ MAGE-A1− cells or IFN-γ-treated HLA-A*0201− MAGE-A1+ cells,were killed by these CTLs. Thus,the combination of HLA epitope prediction,peptide analysis,and immunological methods is a powerful approach for the identification of tumor-associated epitopes.
2- Mao Y. et al. J. Hematol. Oncol. 12(106) (2019)
BACKGROUND: Cancer/testis antigens (CTAs) are a special type of tumor antigen and are believed to act as potential targets for cancer immunotherapy.
METHODS: In this study,we first screened a rational CTA MAGE-A1 for lung adenocarcinoma (LUAD) and explored the detailed characteristics of MAGE-A1 in LUAD development through a series of phenotypic experiments. Then,we developed a novel MAGE-A1-CAR-T cell (mCART) using lentiviral vector based on our previous MAGE-A1-scFv. The anti-tumor effects of this mCART were finally investigated in vitro and in vivo.
RESULTS: The results showed striking malignant behaviors of MAGE-A1 in LUAD development,which further validated the rationality of MAGE-A1 as an appropriate target for LUAD treatment. Then,the innovative mCART was successfully constructed,and mCART displayed encouraging tumor-inhibitory efficacy in LUAD cells and xenografts.
CONCLUSION: Taken together,our data suggest that MAGE-A1 is a promising candidate marker for LUAD therapy and the MAGE-A1-specific CAR-T cell immunotherapy may be an effective strategy for the treatment of MAGE-A1-positive LUAD.
3- Chaux P. et al. J Immunol. 163(5):2928-2936 (1999)
MAGE genes are expressed by many human tumors of different histological types but not by normal cells,except for male germline cells. The Ags encoded by MAGE genes and recognized by T cells are therefore strictly tumor-specific. Clinical trials involving therapeutic vaccination of cancer patients with MAGE antigenic peptides or proteins are in progress. To increase the range of patients eligible for therapy with peptides,it is important to identify additional MAGE epitopes recognized by CTL. Candidate peptides known to bind to a given HLA have been used to stimulate T lymphocytes in vitro. In some instances,CTL clones directed against these synthetic peptides have been obtained,but these clones often failed to recognize tumor cells expressing the relevant gene. Therefore,we designed a method to identify CTL epitopes that selects naturally processed peptides. Monocyte-derived dendritic cells infected with a recombinant canarypoxvirus (ALVAC) containing the entire MAGE-A1 gene were used to stimulate CD8+ T lymphocytes from the blood of individuals without cancer. Responder cell microcultures that specifically lysed autologous cells expressing MAGE-A1 were cloned using autologous stimulator cells either transduced with a retrovirus coding for MAGE-A1 or infected with recombinant Yersinia-MAGE-A1 bacteria. The CTL clones were tested for their ability to lyse autologous cells loaded with each of a set of overlapping MAGE-A1 peptides. This strategy led to the identification of five new MAGE-A1 epitopes recognized by CTL clones on HLA-A3,-A28,-B53,-Cw2,and -Cw3 molecules. All of these CTL clones recognized target cells expressing gene MAGE-A1.
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