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Systemic cancer immunotherapy with Toll-like receptor 7 agonists: Timing is everything.

Hotz C, Bourquin C - Oncoimmunology (2012)

Bottom Line: Toll-like receptor (TLR) 7 agonists represent a promising strategy for the immunotherapy of cancer.We have recently investigated the influence of TLR tolerance on the efficacy of systemic tumor treatment with TLR7 ligands.We propose that considering the kinetics of receptor sensitivity highly improves the outcome of cancer immunotherapy.

View Article: PubMed Central - PubMed

Affiliation: Center for Integrated Protein Science Munich (CIPSM); Division of Clinical Pharmacology; Department of Internal Medicine; Ludwig-Maximilian University of Munich; Munich, Germany ; Department of Medicine; University of Fribourg; Fribourg, Switzerland.

ABSTRACT
Toll-like receptor (TLR) 7 agonists represent a promising strategy for the immunotherapy of cancer. We have recently investigated the influence of TLR tolerance on the efficacy of systemic tumor treatment with TLR7 ligands. We propose that considering the kinetics of receptor sensitivity highly improves the outcome of cancer immunotherapy.

No MeSH data available.


Related in: MedlinePlus

Figure 1. Overview of the cellular mechanisms of TLR7-targeting therapy. DC: dendritic cell, Teff: effector T cells, Treg: regulatory T cell, MDSC: myeloid-derived suppressor cell, NK: natural killer cell, ssRNA: single-stranded RNA.
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Figure 1: Figure 1. Overview of the cellular mechanisms of TLR7-targeting therapy. DC: dendritic cell, Teff: effector T cells, Treg: regulatory T cell, MDSC: myeloid-derived suppressor cell, NK: natural killer cell, ssRNA: single-stranded RNA.

Mentions: Toll-like receptors (TLRs), which sense conserved molecular patterns from microbial pathogens, trigger a cascade of events characterized by the secretion of proinflammatory cytokines that results in the stimulation of innate and adaptive immunity. Agonists of TLRs are therefore of major interest for the immunotherapy of cancer. Imiquimod, a small molecule agonist of TLR7, is already successfully used for the topical treatment of skin neoplasias such as basal cell carcinoma.1 In view of the potential use of TLR7 ligands for the treatment of non-skin cancer, we and others have investigated the ability of TLR7 agonists to induce systemic immune responses. A combined schematic view of the anti-tumor activity of TLR7 agonists as demonstrated by our recent work is depicted in Figure 1. We have shown that the systemic application of TLR7 ligands functionally activates both CD8+ T cells and NK cells, two major effector cell types for anticancer responses.2 Furthermore, TLR7 activation blocks the suppressive function of regulatory T cells that contribute to cancer-associated immune suppression.3 Finally, we have shown that IFN-α produced by plasmacytoid dendritic cells upon TLR activation reduces the immunosuppressive activity of myeloid-derived suppressor cells (MDSC), a cell population that accumulates in cancer patients and suppresses T cell responses.4 We have elucidated the combined molecular basis for these effects by demonstrating that they are mediated by proinflammatory cytokines, in particular IL-6, and type I interferon secreted by dendritic cells following their activation through TLR7.2-4 Thus, TLR7 agonists appear to fulfill many of the requirements for an effective systemic immunotherapy.


Systemic cancer immunotherapy with Toll-like receptor 7 agonists: Timing is everything.

Hotz C, Bourquin C - Oncoimmunology (2012)

Figure 1. Overview of the cellular mechanisms of TLR7-targeting therapy. DC: dendritic cell, Teff: effector T cells, Treg: regulatory T cell, MDSC: myeloid-derived suppressor cell, NK: natural killer cell, ssRNA: single-stranded RNA.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3376978&req=5

Figure 1: Figure 1. Overview of the cellular mechanisms of TLR7-targeting therapy. DC: dendritic cell, Teff: effector T cells, Treg: regulatory T cell, MDSC: myeloid-derived suppressor cell, NK: natural killer cell, ssRNA: single-stranded RNA.
Mentions: Toll-like receptors (TLRs), which sense conserved molecular patterns from microbial pathogens, trigger a cascade of events characterized by the secretion of proinflammatory cytokines that results in the stimulation of innate and adaptive immunity. Agonists of TLRs are therefore of major interest for the immunotherapy of cancer. Imiquimod, a small molecule agonist of TLR7, is already successfully used for the topical treatment of skin neoplasias such as basal cell carcinoma.1 In view of the potential use of TLR7 ligands for the treatment of non-skin cancer, we and others have investigated the ability of TLR7 agonists to induce systemic immune responses. A combined schematic view of the anti-tumor activity of TLR7 agonists as demonstrated by our recent work is depicted in Figure 1. We have shown that the systemic application of TLR7 ligands functionally activates both CD8+ T cells and NK cells, two major effector cell types for anticancer responses.2 Furthermore, TLR7 activation blocks the suppressive function of regulatory T cells that contribute to cancer-associated immune suppression.3 Finally, we have shown that IFN-α produced by plasmacytoid dendritic cells upon TLR activation reduces the immunosuppressive activity of myeloid-derived suppressor cells (MDSC), a cell population that accumulates in cancer patients and suppresses T cell responses.4 We have elucidated the combined molecular basis for these effects by demonstrating that they are mediated by proinflammatory cytokines, in particular IL-6, and type I interferon secreted by dendritic cells following their activation through TLR7.2-4 Thus, TLR7 agonists appear to fulfill many of the requirements for an effective systemic immunotherapy.

Bottom Line: Toll-like receptor (TLR) 7 agonists represent a promising strategy for the immunotherapy of cancer.We have recently investigated the influence of TLR tolerance on the efficacy of systemic tumor treatment with TLR7 ligands.We propose that considering the kinetics of receptor sensitivity highly improves the outcome of cancer immunotherapy.

View Article: PubMed Central - PubMed

Affiliation: Center for Integrated Protein Science Munich (CIPSM); Division of Clinical Pharmacology; Department of Internal Medicine; Ludwig-Maximilian University of Munich; Munich, Germany ; Department of Medicine; University of Fribourg; Fribourg, Switzerland.

ABSTRACT
Toll-like receptor (TLR) 7 agonists represent a promising strategy for the immunotherapy of cancer. We have recently investigated the influence of TLR tolerance on the efficacy of systemic tumor treatment with TLR7 ligands. We propose that considering the kinetics of receptor sensitivity highly improves the outcome of cancer immunotherapy.

No MeSH data available.


Related in: MedlinePlus