title: Introduction of the CIITA gene into tumor cells produces exosomes with enhanced anti-tumor effects.
abstract: Exosomes are small membrane vesicles secreted from various types of cells. Tumor-derived exosomes contain MHC class I molecules and tumor-specific antigens, receiving attention as a potential cancer vaccine. For induction of efficient anti-tumor immunity, CD4+ helper T cells are required, which recognize appropriate MHC class II-peptide complexes. In this study, we have established an MHC class II molecule-expressing B16F1 murine melanoma cell line (B16F1- CIITA) by transduction of the CIITA (Class II transactivator) gene. Exosomes from B16-CII cells (CIITA- Exo) contained a high amount of MHC class II as well as a tumor antigen TRP2. When loaded on dendritic cells (DCs), CIITA-Exo induced the increased expression of MHC class II molecules and CD86 than the exosomes from the parental cells (Exo). In vitro assays using co-culture of immunized splenocytes and exosome-loaded DCs demonstrated that CIITA-Exo enhanced the splenocyte proliferation and IL-2 secretion. Consistently, compared to B16-Exo, CIITA-Exo induced the increased mRNA levels of inflammatory cytokines such as TNF-α, chemokine receptor CCR7 and the production of Th1-polarizing cytokine IL-12. A tumor preventive model showed that CIITA-Exo significantly inhibited tumor growth in a dose-dependent manner. Ex vivo assays using immunized mice demonstrated that CIITA-Exo induced a higher amount of Th1-polarized immune responses such as Th1-type IgG2a antibodies and IFN-γ cytokine as well as TRP2-specific CD8+ T cells. A tumor therapeutic model delayed effects of tumor growth by CIITA-Exo. These findings indicate that CIITA-Exo are more efficient as compared to parental Exo to induce anti-tumor immune responses, suggesting a potential role of MHC class II-containing tumor exosomes as an efficient cancer vaccine.
authors.affiliation: Tumor Immunity Medical Research Center, Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Yeong Shin
authors.initials: YS
authors.lastname: Lee
authors.forename: Soo Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Jung Ah
authors.initials: JA
authors.lastname: Cho
authors.forename: Chul Woo
authors.initials: CW
authors.lastname: Kim
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology; D055354:Exosomes / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D007111:Immunity, Cellular / Q000276:immunology; D056724:Immunity, Humoral / Q000276:immunology; D007167:Immunotherapy; D008213:Lymphocyte Activation / Q000276:immunology; D008546:Melanoma, Experimental / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*; D014161:Transduction, Genetic
chemical_list: D019496:Cancer Vaccines; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators