HCA587 (also known as MAGE-C2) is a “cancer-testis” antigen highly expressed in a number of malignancies with unique immunological properties, making it a promising target for tumor immunotherapy. In this report, we demonstrated that HCA587 protein, when formulated with adjuvants CpG–containing oligodeoxynucleotides (CpG ODN) and ISCOM, was capable of inducing a potent cellular and humoral immune response as indicated by the presence of a large number of HCA587-specific, IFN-γ-producing CD4+ T cells and high levels of HCA587-specific antibodies. More importantly, vaccination with HCA587 conferred protection against challenge with HCA587-expressing B16 melanoma in prophylactic and therapeutic settings. In analysis of the mechanisms underlying the protective effect, we showed that the vaccination was followed by enhanced accumulation of tumor-infiltrating lymphocytes (TILs) with enrichment of conventional CD4+ T cells but reduced representation of Treg cells. Further, the antitumor effect was largely abrogated in mice either depleted of CD4+ T cells or deficient for IFN-γ. These results indicate that HCA587 protein vaccine possesses evident antitumor activity in a mouse model and holds promise for treatment of human cancers.
The cancer testis antigen HCA587 is an attractive candidate for T cell-based immunotherapy because it is overexpressed in a wide spectrum of malignant tumors but not normal tissues, except testis. Several CTL epitopes derived from HCA587 have been described. Our aim was to identify helper T lymphocyte epitopes of HCA587 for the optimization of T cell-based immunotherapies against HCA587-expressing tumors. Candidate helper T lymphocyte epitopes for HCA587 were predicted using the SYFPEITHI algorithm and were tested for their ability to induce helper T lymphocyte responses by in vitro peptide vaccination of CD4 + T lymphocytes from healthy individuals and hepatocellular carcinoma patients. Four CD4 + T-cell epitopes for HCA587 (p43-57, p145-159, p186-200 and p249-263) were identified. Among them, the p43-57 epitope was shown to be naturally processed and presented by HCA587-expressing tumor cells as well as autologous dendritic cells pulsed with whole-protein HCA587. Notably, this epitope behaved as a promiscuous T-cell epitope as it stimulated T cells in the context of more than one HLA class II allele. Thus, p43-57 is the first HCA587-derived major histocompatibility complex class II-restricted epitope to fulfil all prerequisites for use as a peptide vaccine in patients with HCA587-expressing tumors. (Cancer Sci 2011; 102: 1455-1461 T he importance of T cell-mediated antitumor immunity has been demonstrated in both animal models and human cancer therapy.(1,2) Activation of antitumor T-cell immunity relies on the recognition of tumor-associated antigens that bear immunogenic T-cell epitopes expressed on tumor cells. Most attempts have focused on the activation of tumor-specific cytotoxic T lymphocytes (CTL) as they can directly kill tumor cells. Human clinical trials using molecularly defined major histocompatibility complex (MHC) class I-restricted tumor antigens have indicated that antigen-specific T-cell responses are readily detected in patients after vaccination, but overall immune responses are weak and transient. (3)(4)(5) One of the possible explanations is that these immunotherapies have ignored the role that CD4 + T helper lymphocytes play in the generation and persistence of CD8 + Tcell responses. (6,7) Increasing evidence from both human and animal studies indicates that CD4 + T cells play a central role in initiating and maintaining host immune responses against cancer.(8-10) Even in the absence of CTL, tumor regression can be mediated by direct and indirect killing mechanisms.(11-13) Thus, an optimal vaccination might require the participation of both CD4 + and CD8 + T cells to generate a strong and long-lasting antitumor response.Until now, many tumor-specific MHC class I-restricted epitopes have been identified; however, only a very small number of tumor-specific helper T-cell epitopes have been characterized. (14) The lack of MHC class II-restricted helper T epitopes is a major hurdle in the use of antigen-specific CD4 + T cells in cancer vaccines. Thus, identification of MHC class II-restricted...
Hepatocellular carcinoma-associated antigen 587/melanoma antigen gene (HCA587/MAGEC2) is a cancer‑testis antigen, which is highly expressed in various types of tumors, but not in normal tissues with the exception of male germ‑line cells. HCA587/MAGEC2 has been previously recognized as a tumor‑specific target for immunotherapy; however, its biological functions have been relatively understudied. To investigate the function of HCA587/MAGEC2, the amino acid sequence of HCA587/MAGEC2 was analyzed by bioinformatics and it was demonstrated that HCA587/MAGEC2 contains a 9‑amino acid transactivation domain which may mediate the interaction of most transcription factors with TATA‑box binding protein associated factor 9 (TAF9), a general transcription coactivator. Co‑immunoprecipitation experiments revealed that HCA587/MAGEC2 interacted with TAF9 in transfected 293T and in A375 melanoma cells endogenously expressing HCA587/MAGEC2, and confirmed the endogenous interaction of HCA587/MAGEC2 and TAF9 within cells. Endogenous HCA587/MAGEC2 and TAF9 were demonstrated to be co‑localized principally in the nucleus of tumor cells using immunofluorescence. Glutathione-S-transferase pull‑down experiments demonstrated that HCA587/MAGEC2 interacts with TAF9 directly and the conserved region in the TAF9 may becrucial for HCA587/MAGEC2 binding. The present study demonstrated that the cancer‑testis antigen HCA587/MAGEC2 directly interacted with TAF9, which may provide novel information for identifying the oncogenic functions of HCA587/MAGEC2 in tumor cells.
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