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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.
AuthorsYeong Shin Lee, Soo Hyun Kim, Jung Ah Cho, Chul Woo Kim
JournalExperimental & molecular medicine (Exp Mol Med) Vol. 43 Issue 5 Pg. 281-90 (May 31 2011) ISSN: 2092-6413 [Electronic] United States
PMID21464590 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cancer Vaccines
  • MHC class II transactivator protein
  • Nuclear Proteins
  • Trans-Activators
Topics
  • Animals
  • Cancer Vaccines (genetics, immunology)
  • Cell Line, Tumor
  • Cell Proliferation
  • Dendritic Cells (immunology)
  • Exosomes (genetics, metabolism)
  • Gene Expression Regulation
  • Gene Transfer Techniques
  • Immunity, Cellular (immunology)
  • Immunity, Humoral (immunology)
  • Immunotherapy
  • Lymphocyte Activation (immunology)
  • Melanoma, Experimental (mortality, pathology, physiopathology)
  • Mice
  • Mice, Inbred C57BL
  • Nuclear Proteins (genetics, metabolism)
  • Survival Analysis
  • T-Lymphocytes (immunology, metabolism)
  • Trans-Activators (genetics, metabolism)
  • Transduction, Genetic

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