Identification of promiscuous HLA‐DR‐restricted CD4⁺ T‐cell epitopes on the cancer‐testis antigen HCA587

Abstract

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...

Induction of HCA587-Specific Antitumor Immunity with HCA587 Protein Formulated with CpG and ISCOM in Mice

“…To date, nine cytotoxic T lymphocyte (CTL) and four help T cell (Th) epitopes derived from HCA587 have been identified [13], [14], [15], [16], [17], [18]. HCA587 is abnormally expressed in a wide variety of malignancies, including hepatocellular carcinoma, melanoma, bladder cancer, breast cancer, sarcoma and lung cancer, etc [19], [20], [21].…”

Cancer‑testis antigen HCA587/MAGEC2 interacts with the general transcription coactivator TAF9 in cancer cells

“…HCA587/MAGEC2 has been previously demonstrated to be immunogenic and induce spontaneous antibody and T cell immune responses in cancer patients with HCA587/MAGEC2-expressing tumors (28)(29)(30). To the best of our knowledge, 9 CTL and 4 Th epitopes have been identified by the present authors and others (30)(31)(32). Previous studies demonstrated that MAGEC2 expression in cancer cells correlated with their metastatic potential (18,22,33,34).…”

Identification of Melanoma-reactive CD4+ T-Cell Subsets From Human Melanoma Draining Lymph Nodes

“…For examples, immunotherapy using tumor-specific CD8 + T cells in CD4-deficient MHC II −/− mice resulted in regression of pulmonary metastases, but did not result in long-term antitumor immunity and tumor eventually recurred (26, 27). Two studies using MART-1 and/or gp-100-specific HLA class I restricted TCR gene transfer for treatment of metastatic melanoma patients resulted in objective clinical response rates of 13% (2/15) and 30% (6/30), which were lower than the response rates achieved using bulk CD4 + and CD8 + tumor infiltrating T cells (TILs) (51–71%) (28–31). These suggest a therapeutic benefit of using tumor-reactive CD4 + T cells for ACI.…”