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Enhancement of Tumor-Specific T Cell-Mediated Immunity in Dendritic Cell-Based Vaccines by Mycobacterium tuberculosis Heat Shock Protein X

Authors
Jung, In DukShin, Sung JaeLee, Min-GooKang, Tae HeungHan, Hee DongLee, Seung JunKim, Woo SikKim, Hong MinPark, Won SunKim, Han WoolYun, Cheol-HeuiLee, Eun KyungWu, T. -C.Park, Yeong-Min
Issue Date
1-8월-2014
Publisher
AMER ASSOC IMMUNOLOGISTS
Citation
JOURNAL OF IMMUNOLOGY, v.193, no.3, pp.1233 - 1245
Indexed
SCIE
SCOPUS
Journal Title
JOURNAL OF IMMUNOLOGY
Volume
193
Number
3
Start Page
1233
End Page
1245
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/97721
DOI
10.4049/jimmunol.1400656
ISSN
0022-1767
Abstract
Despite the potential for stimulation of robust antitumor immunity by dendritic cells (DCs), clinical applications of DC-based immunotherapy are limited by the low potency in generating tumor Ag-specific T cell responses. Therefore, optimal conditions for generating potent immunostimulatory DCs that overcome tolerance and suppression are key factors in DC-based tumor immunotherapy. In this study, we demonstrate that use of the Mycobacterium tuberculosis heat shock protein X (HspX) as an immunoadjuvant in DC-based tumor immunotherapy has significant potential in therapeutics. In particular, the treatment aids the induction of tumor-reactive T cell responses, especially tumor-specific CTLs. The HspX protein induces DC maturation and proinflammatory cytokine production (TNF-alpha, IL-1 beta, IL-6, and IFN-beta) through TLR4 binding partially mediated by both the MyD88 and the TRIF signaling pathways. We employed two models of tumor progression and metastasis to evaluate HspX-stimulated DCs in vivo. The administration of HspX-stimulated DCs increased the activation of naive T cells, effectively polarizing the CD4(+) and CD8(+) T cells to secrete IFN-gamma, as well as enhanced the cytotoxicity of splenocytes against HPV-16 E7 (E7)-expressing TC-1 murine tumor cells in therapeutic experimental animals. Moreover, the metastatic capacity of B16-BL6 melanoma cancer cells toward the lungs was remarkably attenuated in mice that received HspX-stimulated DCs. In conclusion, the high therapeutic response rates with tumor-targeted Th1-type T cell immunity as a result of HspX-stimulated DCs in two models suggest that HspX harnesses the exquisite immunological power and specificity of DCs for the treatment of tumors.
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