HER-2, gp100, and MAGE-1 Are Expressed in Human Glioblastoma and Recognized by Cytotoxic T Cells

Abstract

It has recently been demonstrated that malignant glioma cells express certain known tumor-associated antigens, such as HER-2, gp100, and MAGE-1. To further determine the possible utilization of these antigens for glioma immunotherapy and as surrogate markers for specific tumor antigen cytotoxicity, we characterized the presence of mRNA and protein expression in 43 primary glioblastoma multiforme (GBM) cell lines and 7 established human GBM cell lines. HER-2, gp100, and MAGE-1 mRNA expression was detected in 81.4%, 46.5%, and 39.5% of the GBM primary cell lines, respectively. Using immunoreactive staining analysis by flow cytometry, HER-2, gp100, and MAGE-1 protein expression was detected in 76%, 45%, and 38% of the GBM primary cell lines, respectively. HLA-A1-restricted epitope specific for MAGE-1 peptide (EADPTGHSY) CTL clone B07 and HLA-A2-restricted epitope specific for HER-2 peptide (KIFGSLAFL) CTL clone A05 and gp100 peptide (ITDQVPFSV) CTL clone CK3H6 were used in this study. The specificity of CTL clone was verified by HLA/peptide tetramer staining. Three CTL clones could efficiently recognize GBM tumor cells in an antigen-specific and MHC class I-restricted manner. IFN-␥ treatment can dramatically increase MHC class I expression of GBM tumor cells and significantly increase CTL recognition of tumor cells. Treatment with the DNA hypomethylating agent 5-aza-2-deoxycytidine induced and up-regulated the mRNA expression of MAGE-1 and epitope presentation by autologous MHC. These data indicate that HER-2, gp100, and MAGE-1 could be used as tumor antigen targets for surrogate assays for antigen-specific CTLs or to develop antigen-specific active immunotherapy strategies for glioma patients.

Identification of SOX2 as a novel glioma-associated antigen and potential target for T cell-based immunotherapy

“…So far, T-cell epitopes derived from SART-1 and -3 (Imaizumi et al, 1999;Murayama et al, 2000), IL-13 receptor a2 chain (Okano et al, 2002), ADPribosylation factor 4-like (ARF4L) , UDP-Gal: betaGlcNAc beta1, 3-galactosyltransferase, polypeptide 3 (GALT3) , AIM-2 (Liu et al, 2004a), EphA2 (Hatano et al, 2005) and the type III variant of the epidermal growth factor receptor (EGFRvIII) (Wu et al, 2006) have been described. In addition, it has been shown that HER-2, gp100, MAGE-1 and TRP-2 were expressed in glioma and were recognised by CTLs (Liu et al, 2003(Liu et al, , 2004b. However, the suitability of some candidates for specific immunotherapy of glioma is limited.…”

“…Thus, ARF4L and GALT3 were markedly expressed in various normal tissues Tsuda et al, 2002) bearing the potential risk of autoimmune reactions. In addition, gp100, MAGE-1, TRP-2 and EGFRvIII were detectable only in a part of gliomas restricting the number of potentially treatable patients (Chi et al, 1997;Liu et al, 2003Liu et al, , 2004bBiernat et al, 2004). Owing to these limitations of several glioma-associated antigens and the heterogeneity of different types of malignant glioma (Chi et al, 1997;Nagane et al, 1997;Liang et al, 2005), the identification of additional target structures for CTLs is required.…”

Regulation of high molecular weight-melanoma associated antigen (HMW-MAA) gene expression by promoter DNA methylation in human melanoma cells

“…On the other hand, in vivo treatment of HMW-MAAnegative melanoma lesions with DAC or other epigenetic modulators could induce HMW-MAA expression, thus increasing the efficacy of antigen-specific antibodies and T cells. In support of the latter possibility, potentiation of tumor antigen recognition following DAC treatment has been shown in other systems, and may serve as a generally applicable mechanism to increase tumor antigen recognition by the immune system (Serrano et al, 2001;Karpf and Jones, 2002;Liu et al, 2004). However, the possible role of HMW-MAA in tumor metastasis serves as a cautionary note for the use of DNA methyltransferase inhibitors to activate anti-tumor immunity targeting HMW-MAA.…”

Cytotoxic T cell targeting of TRP-2 sensitizes human malignant glioma to chemotherapy

“…Our previous studies have shown that melanomaassociated antigens, such as TRP-2, MAGE-1 and gp100 are not only expressed on glioblastoma tumor cells but also may be naturally processed and recognized by cytotoxic T-cells in an MHC class I restricted manner (Liu et al, 2003(Liu et al, , 2004b. TRP-2 may be a unique target molecule for cancer vaccines because TRP-2 expression is not only a highly immunogenic tumor antigen but is also associated with chemotherapy resistance.…”