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.
Highlights
Introduction of theCIITA gene into tumor cells produces exosomes with enhanced anti-tumor effectsYeong Shin Lee1, Soo Hyun Kim1, Jung Ah Cho1,2,3 and Chul Woo Kim1,3Accepted 25 March 2011 Available Online 5 April 2011Abbreviations: CIITA, MHC class II transcriptional activator; CTL, cytotoxic T lymphocytes; exosomes from the parental cells (Exo), exosomes; Hsc70, heat shock cognate; Hsp70, heat shock proteins; MFI, mean fluorescence intensity; MHC, major histocompatibility complex AbstractExosomes are small membrane vesicles secreted from various types of 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
Our results demonstrated that exosomes from CIITA-transduced tumor cells exhibited greater effects on tumor regression as com pared to the Exo, suggesting CIITA-Exo as a potential vaccine for cancer immunotherapy
Summary
Introduction of theCIITA gene into tumor cells produces exosomes with enhanced anti-tumor effectsYeong Shin Lee, Soo Hyun Kim, Jung Ah Cho and Chul Woo Kim1,3Accepted 25 March 2011 Available Online 5 April 2011Exosomes are small membrane vesicles secreted from various types of cells. CIITA gene into tumor cells produces exosomes with enhanced anti-tumor effects. Tumor-derived exosomes contain MHC class I molecules and tumor-specific antigens, receiving attention as a potential cancer vaccine. Exosomes have be small membrane vesicles (40-100 nm in diameter) that originate from multivesicular bodies that release internal vesicles into the extracellular space by fusion with plasma membranes (Denzer et al, 2000) These vesicles are produced by various cell types including reticulocytes, intestinal epithelial cells, hematopoietic cells as well as tumor cells (Johnstone et al, 1987; Raposo et al, 1996; Zitvogel et al, 1998; Heijnen et al, 1999; van Niel et al, 2001; Blanchard et al, 2002; Skokos et al, 2002). Vol 43(5), 281-290, 2011 inhibited tumor growth by tumor specific T cell responses (Zitvogel et al, 1998)
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