Exp Mol Med.  2011 May;43(5):281-290. 10.3858/emm.2011.43.5.029.

Introduction of the CIITA gene into tumor cells produces exosomes with enhanced anti-tumor effects

• Lee YS
• Kim SH
• Cho JA
• Kim CW

• KMID: 1009967
• DOI: http://doi.org/10.3858/emm.2011.43.5.029

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-alpha, 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-gamma 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.

Keyword

cancer vaccine; CIITA; exosomes; immunotherapy; MHC class II molecules

MeSH Terms

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