Enhancement of tumor-specific T cell-mediated immunity in dendritic cell-based vaccines by mycobacterium tuberculosis heat shock protein X

In Duk Jung, Sung Jae Shin, Min Goo Lee, Tae Heung Kang, Hee Dong Han, Seung Jun Lee, Woo Sik Kim, Hong Min Kim, Won Sun Park, Han Wool Kim, Cheol Heui Yun, Eun Kyung Lee, T. C. Wu, Yeong Min Park

Research output: Contribution to journalArticle

27 Citations (Scopus)

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-a, IL-1b, IL-6, and IFN-b) 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-g, 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.

Original languageEnglish
Pages (from-to)1233-1245
Number of pages13
JournalJournal of Immunology
Volume193
Issue number3
DOIs
Publication statusPublished - 2014 Aug 1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Jung, I. D., Shin, S. J., Lee, M. G., Kang, T. H., Han, H. D., Lee, S. J., Kim, W. S., Kim, H. M., Park, W. S., Kim, H. W., Yun, C. H., Lee, E. K., Wu, T. C., & Park, Y. M. (2014). Enhancement of tumor-specific T cell-mediated immunity in dendritic cell-based vaccines by mycobacterium tuberculosis heat shock protein X. Journal of Immunology, 193(3), 1233-1245. https://doi.org/10.4049/jimmunol.1400656