Reconstituted complexes of mycobacterial HSP70 and EBV LMP2A-derived peptides elicit peptide-specific cytotoxic T lymphocyte responses and anti-tumor immunity

• Published in: Vaccine Vol. 29; no. 43; pp. 7414 - 7423
• Main Authors: Liu, Genyan, Yao, Kun, Wang, Bing, Zhou, Feng, Chen, Yun, Li, Linyun, Chi, Jing, Peng, Guangyong
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 06.10.2011; Elsevier; Elsevier Limited
• Subjects: Adjuvant; Adjuvants; Allergy and Immunology; Animal models; Animals; antigens; Antigens, Bacterial - immunology; Applied microbiology; Bacteriology; Biological and medical sciences; Cancer; Cancer Vaccines - immunology; Carcinoma; Chaperones; Clinical trials; cytotoxic T-lymphocytes; Cytotoxicity; Cytotoxicity, Immunologic; Epstein-Barr virus; Fundamental and applied biological sciences. Psychology; genetically modified organisms; Heat shock protein 70; Herpes viruses; Herpesvirus 4, Human - immunology; Histocompatibility antigen HLA; Hodgkin disease; Hodgkin Disease - immunology; Hodgkin's disease; HSP70 Heat-Shock Proteins - immunology; Hsp70 protein; Human herpesvirus 4; Humans; Immune response; Immunity; Immunotherapy; Interferon-gamma - biosynthesis; Latent membrane protein 2A; LMP2A protein; Lymphocytes; Lymphocytes T; Malignancy; Melanoma; Membrane proteins; Mice; Mice, Transgenic; Microbiology; Miscellaneous; Multiprotein Complexes - immunology; Mycobacterium tuberculosis; Mycobacterium tuberculosis - immunology; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms - immunology; Peptides; Plasmids; Protein folding; Studies; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism; Transgenic mice; Tuberculosis; Tumors; Vaccines; Vaccines, antisera, therapeutical immunoglobulins and monoclonal antibodies (general aspects); Viral Matrix Proteins - immunology; Viral Vaccines - immunology; Virology; Heat shock protein 70; Adjuvant; Latent membrane protein 2A; Immunotherapy; Epstein–Barr virus; Gammaherpesvirinae; Mycobacterium; Membrane protein; Peptides; Herpesviridae; Cytotoxicity; Epstein Barr virus; Malignant tumor; Virus; Mycobacteriales; Immunological adjuvant; T-Lymphocyte; Heat shock protein; Mycobacteriaceae; Bacteria; Actinomycetes; Epstein-Barr virus; Cytotoxic T lymphocyte; Cancer
• ISSN: 0264-410X; 1873-2518
• DOI: 10.1016/j.vaccine.2011.07.063

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 (LMP2A356–364 FLYALALLL and LMP2A426–434 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.