Synergistic activation of dendritic cells by combined Toll-like receptor ligation induces superior CTL responses in vivo

Warger, Tobias; Osterloh, Philipp; Rechtsteiner, Gerd; Fassbender, Melanie; Heib, Valeska; Schmid, Beate; Schmitt, Edgar; Schild, Hansjörg; Radsak, Markus P.

doi:10.1182/blood-2005-10-4015

Cited by 216 publications

(198 citation statements)

References 40 publications

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“…Ag presentation by DCs, in the absence of proper costimulation, induces tolerance (1). In particular, recent studies suggest that TLR-agonist CpG ODNs or conserved pathogen-associated molecular patterns, such as OK-432, start the DC maturation process, which is a critical event in the induction of full effector function in T cells (20,31,32,35,41,57,58). Therefore, we next investigated whether DCs activated by a combination of TLR ligation and up-regulated HSPs enhance the immunogenicity of FCs.…”

Section: Discussionmentioning

confidence: 99%

Section: Synergistic Induction Of Antigen-specific Ctl By Fusions Of mentioning

confidence: 99%

“…The triggering of TLR by pathogen-associated molecular patterns potently induces DC maturation, leading to the production of proinflammatory cytokines and the up-regulation of costimulatory molecules (31,32). Therefore, TLR-mediated signals play an important role in the induction and regulation of antitumor immune responses (31,32). OK-432, a penicillin-killed and lyophilized preparation of a low-virulence strain (Su) of Streptococcus pyogenes (group A), has been used without apparent side effects for Ͼ20 years as an adjuvant for patients with cancer (33)(34)(35).…”

Section: Synergistic Induction Of Antigen-specific Ctl By Fusions Of mentioning

confidence: 99%

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Synergistic Induction of Antigen-Specific CTL by Fusions of TLR-Stimulated Dendritic Cells and Heat-Stressed Tumor Cells

Koido

Hara

Homma

et al. 2007

The Journal of Immunology

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Dendritic cell (DC)/tumor cell fusion cells (FCs) can induce potent CTL responses. The therapeutic efficacy of a vaccine requires the improved immunogenicity of both DCs and tumor cells. The DCs stimulated with the TLR agonist penicillin-killed Streptococcus pyogenes (OK-432; OK-DCs) showed higher expression levels of MHC class I and II, CD80, CD86, CD83, IL-12, and heat shock proteins (HSPs) than did immature DCs. Moreover, heat-treated autologous tumor cells displayed a characteristic phenotype with increased expression of HSPs, carcinoembryonic Ag (CEA), MUC1, and MHC class I (HLA-A2 and/or A24). In this study, we have created four types of FC preparation by alternating fusion cell partners: 1) immature DCs fused with unheated tumor cells; 2) immature DCs fused with heat-treated tumor cells; 3) OK-DCs fused with unheated tumor cells; and 4) OK-DCs fused with heat-treated tumor cells. Although OK-DCs fused with unheated tumor cells efficiently enhanced CTL induction, OK-DCs fused with heat-treated tumor cells were most active, as demonstrated by: 1) up-regulation of multiple HSPs, MHC class I and II, CEA, CD80, CD86, CD83, and IL-12; 2) activation of CD4+ and CD8+ T cells able to produce IFN- γ at higher levels; 3) efficient induction of CTL activity specific for CEA or MUC1 or both against autologous tumor; and 4) superior abilities to induce CD107+IFN-γ+CD8+ T cells and CD154+ IFN-γ+CD4+ T cells. These results strongly suggest that synergism between OK-DCs and heat-treated tumor cells enhances the immunogenicity of FCs and provides a promising means of inducing therapeutic antitumor immunity.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Synergistic Induction Of Antigen-specific Ctl By Fusions Of mentioning

confidence: 99%

Section: Synergistic Induction Of Antigen-specific Ctl By Fusions Of mentioning

confidence: 99%

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Synergistic Induction of Antigen-Specific CTL by Fusions of TLR-Stimulated Dendritic Cells and Heat-Stressed Tumor Cells

Koido

Hara

Homma

et al. 2007

The Journal of Immunology

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“…On triggering of TLR9, DCs mature and migrate to draining lymph nodes where they present antigens to T and B lymphocytes (6). Importantly, mature DCs acquire the unique ability to present captured antigens on MHC class I molecules, a process known as cross-presentation (7), which is crucial for efficient priming of tumor-specific CTLs (8,9). As such, CpG administration has been reported to prevent tumor outgrowth in a prophylactic setting and could also eradicate established tumors in mice (10,11).…”

Section: Introductionmentioning

confidence: 99%

In vivo Colocalization of Antigen and CpG within Dendritic Cells Is Associated with the Efficacy of Cancer Immunotherapy

Nierkens¹,

Brok²,

Sutmuller³

et al. 2008

Cancer Research

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Immunostimulatory cytidyl guanosyl (CpG) motifs are of great interest as cancer vaccine adjuvants. They act as potent inducers of Th1 responses, including the activation of cytotoxic CD8 + T lymphocytes (CTL). Whereas animal models have provided clear evidence that CpG enhances antitumor immunity, clinical trials in humans have thus far been less successful. Applying cryosurgery as an instant in situ tumor destruction technique, we now show that timing of CpG administration crucially affects colocalization of antigen and CpG within EEA-1 + and LAMP-1 + compartments within dendritic cells in vivo. Moreover, antigen/CpG colocalization is directly correlated with antigen cross-presentation, the presence of CTL, and protective antitumor immunity. Thus, failure or success of CpG as a vaccine adjuvant may depend on colocalization of antigen/CpG inside DCs and hence on the timing of CpG administration. These data might aid in the design of future immunotherapeutic strategies for cancer patients. [Cancer Res 2008;68(13):5390-6]

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“…Our data showed that, neurotoxin, some fungal lysates and LPS from the mucosal pathogen Porphyromonas gingivalis bias immune responses towards Th2. [31][32][33][34][35] As there is evidence that TLR synergy can enhance immune responses, [36][37][38][39] the inclusion in a vaccine of multiple TLR agonists may prove highly beneficial. However, the extent to which TLR stimulation, especially that induced by combined TLR agonists, influences immunological potency and the overall Th1/Th2 balance of the immune response is largely unknown.…”

confidence: 99%

Toll-like receptor-mediated adjuvanticity and immunomodulation in dendritic cells: Implications for peptide vaccines

Mitchell

Yong²,

Raju³

et al. 2011

Human Vaccines

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Synergistic activation of dendritic cells by combined Toll-like receptor ligation induces superior CTL responses in vivo

Cited by 216 publications

References 40 publications

Synergistic Induction of Antigen-Specific CTL by Fusions of TLR-Stimulated Dendritic Cells and Heat-Stressed Tumor Cells

Synergistic Induction of Antigen-Specific CTL by Fusions of TLR-Stimulated Dendritic Cells and Heat-Stressed Tumor Cells

In vivo Colocalization of Antigen and CpG within Dendritic Cells Is Associated with the Efficacy of Cancer Immunotherapy

Toll-like receptor-mediated adjuvanticity and immunomodulation in dendritic cells: Implications for peptide vaccines

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