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, SungJae Shin, Yeong Min Park

Research output: Contribution to journalArticle

44 Citations (Scopus)

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

Fingerprint

Cancer Vaccines
Mycobacterium tuberculosis
Dendritic Cells
Th1 Cells
T-Lymphocytes
Immunotherapy
Therapeutics
Cytokines
Thymoma
Interleukin-12
heparin-binding hemagglutinin
Interleukin-1
Immunity
Interleukin-6
Neoplasms
Vaccines
Growth

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Jung, Duk ; Jeong, Soo Kyung ; Lee, Chang Min ; Noh, Kyung Tae ; Heo, Deok Rim ; Shin, Yong Kyoo ; Yun, Cheol Heui ; Koh, Won Jung ; Akira, Shizuo ; Whang, Jake ; Kim, Hwa Jung ; Park, Won Sun ; Shin, SungJae ; Park, Yeong Min. / Enhanced efficacy of therapeutic cancer vaccines produced by Co-treatment with mycobacterium tuberculosis heparin-binding hemagglutinin, a novel TLR4 agonist. In: Cancer Research. 2011 ; Vol. 71, No. 8. pp. 2858-2870.
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title = "Enhanced efficacy of therapeutic cancer vaccines produced by Co-treatment with mycobacterium tuberculosis heparin-binding hemagglutinin, a novel TLR4 agonist",
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 na{\"i}ve 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.",
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Jung, D, Jeong, SK, Lee, CM, Noh, KT, Heo, DR, Shin, YK, Yun, CH, Koh, WJ, Akira, S, Whang, J, Kim, HJ, Park, WS, Shin, S & Park, YM 2011, 'Enhanced efficacy of therapeutic cancer vaccines produced by Co-treatment with mycobacterium tuberculosis heparin-binding hemagglutinin, a novel TLR4 agonist', Cancer Research, vol. 71, no. 8, pp. 2858-2870. https://doi.org/10.1158/0008-5472.CAN-10-3487

Enhanced efficacy of therapeutic cancer vaccines produced by Co-treatment with mycobacterium tuberculosis heparin-binding hemagglutinin, a novel TLR4 agonist. / Jung, Duk; Jeong, Soo Kyung; Lee, Chang Min; Noh, Kyung Tae; Heo, Deok Rim; Shin, Yong Kyoo; Yun, Cheol Heui; Koh, Won Jung; Akira, Shizuo; Whang, Jake; Kim, Hwa Jung; Park, Won Sun; Shin, SungJae; Park, Yeong Min.

In: Cancer Research, Vol. 71, No. 8, 15.04.2011, p. 2858-2870.

Research output: Contribution to journalArticle

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T1 - Enhanced efficacy of therapeutic cancer vaccines produced by Co-treatment with mycobacterium tuberculosis heparin-binding hemagglutinin, a novel TLR4 agonist

AU - Jung, Duk

AU - Jeong, Soo Kyung

AU - Lee, Chang Min

AU - Noh, Kyung Tae

AU - Heo, Deok Rim

AU - Shin, Yong Kyoo

AU - Yun, Cheol Heui

AU - Koh, Won Jung

AU - Akira, Shizuo

AU - Whang, Jake

AU - Kim, Hwa Jung

AU - Park, Won Sun

AU - Shin, SungJae

AU - Park, Yeong Min

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