Enhanced efficacy of therapeutic cancer vaccines produced by Co-treatment with mycobacterium tuberculosis heparin-binding hemagglutinin, a novel TLR4 agonist

Duk Jung, Soo Kyung Jeong, Chang Min Lee, Kyung Tae Noh, Deok Rim Heo, Yong Kyoo Shin, Cheol Heui Yun, Won Jung Koh, Shizuo Akira, Jake Whang, Hwa Jung Kim, Won Sun Park, Sung Jae Shin, Yeong Min Park

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Abstract

Effective activation of dendritic cells (DCs) toward T helper (Th)-1 cell polarization would improve DCbased antitumor immunotherapy, helping promote the development of immunotherapeutic vaccines based on T-cell immunity. To achieve this goal, it is essential to develop effective immune adjuvants that can induce powerful Th1 cell immune responses. The pathogenic organism Mycobacterium tuberculosis includes certain constitutes, such as heparin-binding hemagglutinin (HBHA), that possess a strong immunostimulatorypotential. In this study, we report the first clarification of the functions and precise mechanism of HBHA in immune stimulation settings relevant to cancer. HBHA induced DCmaturation in a TLR4-dependent manner, elevating expression of the surface molecules CD40, CD80, and CD86, MHC classes I and II and the proinflammatory cytokines IL-6, IL-12, IL-1β , TNF-α, and CCR7, as well as stimulating the migratory capacity of DCs in vitro and in vivo. Mechanistic investigations established that MyD88 and TRIF signaling pathways downstream of TLR4 mediated secretion of HBHA-induced proinflammatory cytokines. HBHA-treated DCs activated naïve T cells, polarized CD4+ and CD8+ T cells to secrete IFN-g, and induced T-cell-mediated cytotoxicity. Notably, systemic administration of DCs that were HBHA-treated and OVA251-264-pulsed ex vivo greatly strengthened immune priming in vivo, inducing a dramatic regression of tumor growth associated with long-term survival in a murine E.G7 thymoma model. Together, our findings highlight HBHA as an immune adjuvant that favors Th1 polarization and DC function for potential applications in DC-based antitumor immunotherapy.

Original languageEnglish
Pages (from-to)2858-2870
Number of pages13
JournalCancer Research
Volume71
Issue number8
DOIs
Publication statusPublished - 2011 Apr 15

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All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Jung, D., Jeong, S. K., Lee, C. M., Noh, K. T., Heo, D. R., Shin, Y. K., Yun, C. H., Koh, W. J., Akira, S., Whang, J., Kim, H. J., Park, W. S., Shin, S. J., & Park, Y. M. (2011). Enhanced efficacy of therapeutic cancer vaccines produced by Co-treatment with mycobacterium tuberculosis heparin-binding hemagglutinin, a novel TLR4 agonist. Cancer Research, 71(8), 2858-2870. https://doi.org/10.1158/0008-5472.CAN-10-3487