title: Tumor cells transduced with the MHC class II Transactivator and CD80 activate tumor-specific CD4+ T cells whether or not they are silenced for invariant chain.
abstract: The specificity and potency of the immune system make immunotherapy a potential strategy for the treatment of cancer. To exploit this potential, we have developed cell-based cancer vaccines consisting of tumor cells expressing syngeneic MHC class II and costimulatory molecules. The vaccines mediate tumor regression in mice and activate human CD4+ T cells in vitro. Previous vaccines were generated by transducing MHC II negative tumor cells with a single HLA-DR allele. Because expression of multiple MHC II alleles would facilitate presentation of a broader repertoire of tumor antigens, we have now transduced tumor cells with the MHC class II transactivator (CIITA), a regulatory gene that coordinately increases expression of all MHC II alleles. Previous studies in mice indicated that coexpression of the MHC II accessory molecule invariant chain (Ii) inhibited presentation of endogenously synthesized tumor antigens and reduced vaccine efficacy. To determine if Ii expression affects presentation of MHC class II-restricted endogenously synthesized tumor antigens in human tumor cells, HLA-DR-MCF10 breast cancer cells were transduced with the CIITA, CD80 costimulatory molecule gene, and with or without small interfering RNAs (siRNA) specific for Ii. Ii expression is silenced >95% in CIITA/CD80/siRNA transductants; down-regulation of Ii does not affect HLA-DR expression or stability; and Ii(+) and Ii(-) transductants activate human CD4+ T cells to DRB1*0701-restricted HER-2/neu epitopes. Therefore, tumor cells transduced with the CIITA, CD80, and with or without Ii siRNA present endogenously synthesized tumor antigens and are potential vaccines for activating tumor-specific CD4+ T cells.
authors.affiliation: Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Thompson
authors.forename: Samudra K
authors.initials: SK
authors.lastname: Dissanayake
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Ksander
authors.forename: Keith L
authors.initials: KL
authors.lastname: Knutson
authors.forename: Mary L
authors.initials: ML
authors.lastname: Disis
authors.forename: Suzanne
authors.initials: S
authors.lastname: Ostrand-Rosenberg
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis; D018122:B7-1 Antigen / Q000276:immunology; D001943:Breast Neoplasms / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D034741:RNA, Small Interfering; D012190:Retroviridae; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D018122:B7-1 Antigen; D019496:Cancer Vaccines; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D015534:Trans-Activators