EphA2 as a Glioma-Associated Antigen: A Novel Target for Glioma Vaccines

Abstract

EphA2 is a receptor tyrosine kinase and is frequently overexpressed in a wide array of advanced cancers. We demonstrate in the current study that the EphA2 protein is restrictedly expressed in primary glioblastoma multiforme and anaplastic astrocytoma tissues in comparison to normal brain tissues. To evaluate the possibility of targeting EphA2 in glioma vaccine strategies, we stimulated human leukocyte antigen (HLA) A2+ peripheral blood mononuclear cells (PBMCs) obtained from healthy donors and glioma patients with autologous dendritic cells (DCs) loaded with synthetic EphA2883-891 peptide (TLADFDPRV), which has previously been reported to induce interferon-gamma in HLA-A2+ PBMCs. Stimulated PBMCs demonstrated antigen-specific cytotoxic T lymphocyte (CTL) responses as detected by specific lysis of T2 cells loaded with the EphA2883 peptide as well as HLA-A2+ glioma cells, SNB19 and U251, that express EphA2. Furthermore, in vivo immunization of HLA-A2 transgenic HHD mice with the EphA2883-891 peptide resulted in the development of an epitope-specific CTL response in splenocytes, despite the fact that EphA2883-891 is an autoantigen in these mice. Taken together, these data suggest that EphA2883-891 may be an attractive antigen epitope for molecularly targeted glioma vaccines.

Expression of glioma-associated antigens in pediatric brain stem and non-brain stem gliomas

“…We have previously reported that EphA2 883-891 can elicit an HLA-A2-restricted CTL response against glioma cell lines [20]. In addition, recent studies from us [20] and others [32] have revealed that a majority of adult malignant gliomas express high levels of EphA2. More recently, EphA2 mRNA overexpression was found to correlate inversely with survival in a panel of 21 adult GBM cases, and ligand-mediated EphA2 receptor activation increased GBM cell proliferation via a mitogen-activated protein kinase-dependent pathway [33].…”

“…We chose to evaluate these three antigens because they are expressed in adult gliomas and are known to contain CTL epitopes, especially in the context of HLA-A2 [18,20,23]. Our results suggest that EphA2, IL-13α2 and Survivin are suitable targets for developing vaccine strategies for pediatric glioma.…”

“…EphA2 is frequently overexpressed and often functionally dysregulated in advanced cancers, contributing to their malignant phenotype [31]. We have previously reported that EphA2 883-891 can elicit an HLA-A2-restricted CTL response against glioma cell lines [20]. In addition, recent studies from us [20] and others [32] have revealed that a majority of adult malignant gliomas express high levels of EphA2.…”

“…In contrast, vaccines in the form of synthetic peptides encoding T-cell epitopes in GAA would eliminate the need for autologous fresh glioma explants to generate clinical grade vaccines, facilitate timely vaccine production, and potentially reduce the risk of autoimmune encephalitis. To this end, we have focused attention on the identification and characterization of human GAA-derived cytotoxic T-lymphocyte (CTL) epitopes, such as those in the interleukin-13 receptor (IL-13R)α2 [18,19] and EphA2 [20]. Recent studies by others have shown that Survivin, which contains HLA-A2-restricted CTL epitopes [21,22], are frequently expressed at high levels in grade II, III and IV astrocytomas in adults [23].…”

Patterns of EphA2 protein expression in primary and metastatic pancreatic carcinoma and correlation with genetic status

“…Instead, ephrinA binding seems to regulate EphA2 subcellular localization and interaction with other downstream signaling proteins including FAK and the MAP/ERK signaling pathways [8,9]. EphA2 is overexpressed in a variety of human cancers, and high levels of EphA2 are associated with aggressive disease and poor clinical outcomes [10][11][12][13][14][15][16][17][18][19]. In vitro studies have shown that EphA2 is a powerful oncoprotein, sufficient to confer malignant potential on non-transformed epithelial cells [7].…”