title: Reconstituted complexes of mycobacterial HSP70 and EBV LMP2A-derived peptides elicit peptide-specific cytotoxic T lymphocyte responses and anti-tumor immunity.
abstract: Epstein-Barr virus (EBV) latent membrane protein 2A (LMP2A) is a subdominant antigen expressed in EBV-associated malignancies, such as Hodgkin's diseases (HD) and nasopharyngeal carcinoma. A large number of previous studies have described LMP2A as an ideal target antigen in immunotherapy of EBV-related diseases, while limited successes have been achieved in clinical trials. Mycobacterium tuberculosis heat shock protein 70 (MtHsp70) is known as an effective molecular adjuvant for protein- or epitope-based vaccines. In the present study, we reconstituted two chaperone complexes of MtHsp70 and LMP2A-derived peptides (LMP2A(356-364) FLYALALLL and LMP2A(426-434) CLGGLLTMV) in vitro. We then investigated LMP2A-specific immune responses induced by reconstituted complexes of MtHsp70 and LMP2A-peptides using both EBV infected healthy donor PBMCs and HLA-A2.1 transgenic mouse models. We found that reconstituted complexes of MtHsp70 and LMP2A-peptides significantly elicit LMP2A-specific IFN-γ-producing cells and rousted cytotoxic T lymphocytes (CTLs) in vitro and in vivo. In addition, LMP2A-specific immune responses induced by the reconstituted complexes of MtHsp70 and LMP2A-peptides mediated potently protective activity as well as therapeutic efficacy against LMP2A-expressed tumor challenge in mouse models. These studies provide new insights for the development of novel LMP2A-based vaccines against EBV-associated malignancies.
authors.affiliation: Department of Microbiology and Immunology, Nanjing Medical University, Nanjing 210029, PR China.
authors.forename: Genyan
authors.initials: G
authors.lastname: Liu
authors.forename: Kun
authors.initials: K
authors.lastname: Yao
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.forename: Feng
authors.initials: F
authors.lastname: Zhou
authors.forename: Yun
authors.initials: Y
authors.lastname: Chen
authors.forename: Linyun
authors.initials: L
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Chi
authors.forename: Guangyong
authors.initials: G
authors.lastname: Peng
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology; D002277:Carcinoma; D003602:Cytotoxicity, Immunologic; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology*; D004854:Herpesvirus 4, Human / Q000276:immunology; D006689:Hodgkin Disease / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000276:immunology; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000276:immunology*; D014765:Viral Vaccines / Q000276:immunology
chemical_list: D000942:Antigens, Bacterial; D019496:Cancer Vaccines; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D018840:HSP70 Heat-Shock Proteins; D046912:Multiprotein Complexes; D014763:Viral Matrix Proteins; D014765:Viral Vaccines; C072681:Mycobacterium tuberculosis antigens; D007371:Interferon-gamma