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 language | English |
|---|---|
| Pages (from-to) | 2858-2870 |
| Number of pages | 13 |
| Journal | Cancer Research |
| Volume | 71 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - 2011 Apr 15 |
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All Science Journal Classification (ASJC) codes
- Oncology
- Cancer Research
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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, Sung Jae; Park, Yeong Min.
In: Cancer Research, Vol. 71, No. 8, 15.04.2011, p. 2858-2870.Research output: Contribution to journal › Article
TY - JOUR
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, Sung Jae
AU - Park, Yeong Min
PY - 2011/4/15
Y1 - 2011/4/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79954586111&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79954586111&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-10-3487
DO - 10.1158/0008-5472.CAN-10-3487
M3 - Article
C2 - 21368092
AN - SCOPUS:79954586111
VL - 71
SP - 2858
EP - 2870
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 8
ER -