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Application potential of toll-like receptors in cancer immunotherapy: Systematic review.

Shi M, Chen X, Ye K, Yao Y, Li Y - Medicine (Baltimore) (2016)

Bottom Line: Although several potential therapeutic Toll-like receptor ligands have been found, the mechanism and therapy prospect of TLRs in cancer development has to be further elucidated to accelerate the clinical application.In total, 147 full-text articles were assessed, and from these, 54 were excluded as they did not provide complete key information.Thus, 93 studies were considered eligible and included in the analysis.

View Article: PubMed Central - PubMed

Affiliation: School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.

ABSTRACT
Toll-like receptors (TLRs), as the most important pattern recognition receptors in innate immunity, play a pivotal role in inducing immune response through recognition of microbial invaders or specific agonists. Recent studies have suggested that TLRs could serve as important regulators in the development of a variety of cancer. However, increasing evidences have shown that TLRs may display quite opposite outcomes in cancer development. Although several potential therapeutic Toll-like receptor ligands have been found, the mechanism and therapy prospect of TLRs in cancer development has to be further elucidated to accelerate the clinical application. By performing a systematic review of the present findings on TLRs in cancer immunology, we attempted to evaluate the therapeutic potential of TLRs in cancer therapy and elucidate the potential mechanism of cancer progress regulated by TLR signaling and the reported targets on TLRs for clinical application. An electronic databases search was conducted in PubMed, Chinese Scientific Journal Database, and Chinese Biomedical Literature Database from their inception to February 1, 2016. The following keywords were used to search the databases: Toll-like receptors, cancer therapy, therapeutic target, innate immunity. Of 244 studies that were identified, 97 nonrelevant studies were excluded. In total, 147 full-text articles were assessed, and from these, 54 were excluded as they did not provide complete key information. Thus, 93 studies were considered eligible and included in the analysis. According to the data from the included trials, 14 TLR ligands (77.8%) from 82 studies have been demonstrated to display antitumor property in various cancers, whereas 4 ligands (22.2%) from 11 studies promote tumors. Among them, only 3 TLR ligands have been approved for cancer therapy, and 9 ligands were in clinical trials. In addition, the potential mechanism of recently reported targets on TLRs for clinical application was also evaluated in this review. We show that targeting TLRs in cancer immunotherapy is a promising strategy for cancer therapy, and the specific TLR ligands, either alone or combination, exhibit antitumor potential.

No MeSH data available.


Related in: MedlinePlus

A model describing the mechanism of TLRs in cancer therapy. Activation of p53, due to DNA stress or antitumor agents, leads to enhance TLR signaling. Activated TLRs induce autophagy through recruitment of MAP1S and regulation of Bcl-2/XL and p27 in a noncanonical pathway. TLR3 signaling requires RIP1 to activate caspase-3 and caspase-8 and induces apoptosis. TLR5 ligand flagellin induces pyroptosis through introduction into cells by TLR5, and recognition by Naip5/NLRC4 to activate caspase-1. TLRs = toll-like receptors.
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Figure 2: A model describing the mechanism of TLRs in cancer therapy. Activation of p53, due to DNA stress or antitumor agents, leads to enhance TLR signaling. Activated TLRs induce autophagy through recruitment of MAP1S and regulation of Bcl-2/XL and p27 in a noncanonical pathway. TLR3 signaling requires RIP1 to activate caspase-3 and caspase-8 and induces apoptosis. TLR5 ligand flagellin induces pyroptosis through introduction into cells by TLR5, and recognition by Naip5/NLRC4 to activate caspase-1. TLRs = toll-like receptors.

Mentions: Apoptosis is the most efficient TLR-mediated programmed cell death (PCD), which involves activation of catabolic enzymes that lead to cell death through destruction of cell organelles.[79] Estornes et al and Salaun et al illustrated the mechanism of TLR-induced apoptosis that TLR3 ligand dsRNA-induced cell death was through apoptosis directly, which required recruitment of RIP1, caspase-3 and caspase-8.[52,80] Pyroptosis is a form of proinflammatory PCD and is initiated with the recognition of flagellin components. Several groups found that flagellin inhibited breast cancer through induction of caspase-1 activation-dependent pyroptosis, which was activated by the TLR5 and NLRC4/Naip5 signaling pathway.[81–83] Autophagy is another classic TLR-mediated PCD, and it has dual and complicated roles in cancer. In response to nutrient starvation, autophagy produces recycled nutrients to avoid cell death, whereas high level of autophagy constitutes an alternative cell death pathway. Recent study of our lab and other groups showed that autophagy adaptor protein MAP1S involved in TLR signaling, and regulated Bcl-2/XL and p27 to activate autophagy through the noncanonical pathway.[5,84–87] Current novel opinion on tumor suppressor p53 and TLRs showed that p53 modulated TLR signaling in cancer cells. The tumor suppressor p53, in response to stress signals or antitumor agents, induced transcriptional upregulation of individual TLR gene, therefore enhanced TLR downstream signaling in cancer cells (Fig. 2).[53,88] Potential tumor suppressor MARVELD1 (MARVEL domain-containing 1), as a candidate regulator of TLR signaling, inhibits proliferation of cancer cells through regulating the expression of p53 and p16.[89–93]


Application potential of toll-like receptors in cancer immunotherapy: Systematic review.

Shi M, Chen X, Ye K, Yao Y, Li Y - Medicine (Baltimore) (2016)

A model describing the mechanism of TLRs in cancer therapy. Activation of p53, due to DNA stress or antitumor agents, leads to enhance TLR signaling. Activated TLRs induce autophagy through recruitment of MAP1S and regulation of Bcl-2/XL and p27 in a noncanonical pathway. TLR3 signaling requires RIP1 to activate caspase-3 and caspase-8 and induces apoptosis. TLR5 ligand flagellin induces pyroptosis through introduction into cells by TLR5, and recognition by Naip5/NLRC4 to activate caspase-1. TLRs = toll-like receptors.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4998329&req=5

Figure 2: A model describing the mechanism of TLRs in cancer therapy. Activation of p53, due to DNA stress or antitumor agents, leads to enhance TLR signaling. Activated TLRs induce autophagy through recruitment of MAP1S and regulation of Bcl-2/XL and p27 in a noncanonical pathway. TLR3 signaling requires RIP1 to activate caspase-3 and caspase-8 and induces apoptosis. TLR5 ligand flagellin induces pyroptosis through introduction into cells by TLR5, and recognition by Naip5/NLRC4 to activate caspase-1. TLRs = toll-like receptors.
Mentions: Apoptosis is the most efficient TLR-mediated programmed cell death (PCD), which involves activation of catabolic enzymes that lead to cell death through destruction of cell organelles.[79] Estornes et al and Salaun et al illustrated the mechanism of TLR-induced apoptosis that TLR3 ligand dsRNA-induced cell death was through apoptosis directly, which required recruitment of RIP1, caspase-3 and caspase-8.[52,80] Pyroptosis is a form of proinflammatory PCD and is initiated with the recognition of flagellin components. Several groups found that flagellin inhibited breast cancer through induction of caspase-1 activation-dependent pyroptosis, which was activated by the TLR5 and NLRC4/Naip5 signaling pathway.[81–83] Autophagy is another classic TLR-mediated PCD, and it has dual and complicated roles in cancer. In response to nutrient starvation, autophagy produces recycled nutrients to avoid cell death, whereas high level of autophagy constitutes an alternative cell death pathway. Recent study of our lab and other groups showed that autophagy adaptor protein MAP1S involved in TLR signaling, and regulated Bcl-2/XL and p27 to activate autophagy through the noncanonical pathway.[5,84–87] Current novel opinion on tumor suppressor p53 and TLRs showed that p53 modulated TLR signaling in cancer cells. The tumor suppressor p53, in response to stress signals or antitumor agents, induced transcriptional upregulation of individual TLR gene, therefore enhanced TLR downstream signaling in cancer cells (Fig. 2).[53,88] Potential tumor suppressor MARVELD1 (MARVEL domain-containing 1), as a candidate regulator of TLR signaling, inhibits proliferation of cancer cells through regulating the expression of p53 and p16.[89–93]

Bottom Line: Although several potential therapeutic Toll-like receptor ligands have been found, the mechanism and therapy prospect of TLRs in cancer development has to be further elucidated to accelerate the clinical application.In total, 147 full-text articles were assessed, and from these, 54 were excluded as they did not provide complete key information.Thus, 93 studies were considered eligible and included in the analysis.

View Article: PubMed Central - PubMed

Affiliation: School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.

ABSTRACT
Toll-like receptors (TLRs), as the most important pattern recognition receptors in innate immunity, play a pivotal role in inducing immune response through recognition of microbial invaders or specific agonists. Recent studies have suggested that TLRs could serve as important regulators in the development of a variety of cancer. However, increasing evidences have shown that TLRs may display quite opposite outcomes in cancer development. Although several potential therapeutic Toll-like receptor ligands have been found, the mechanism and therapy prospect of TLRs in cancer development has to be further elucidated to accelerate the clinical application. By performing a systematic review of the present findings on TLRs in cancer immunology, we attempted to evaluate the therapeutic potential of TLRs in cancer therapy and elucidate the potential mechanism of cancer progress regulated by TLR signaling and the reported targets on TLRs for clinical application. An electronic databases search was conducted in PubMed, Chinese Scientific Journal Database, and Chinese Biomedical Literature Database from their inception to February 1, 2016. The following keywords were used to search the databases: Toll-like receptors, cancer therapy, therapeutic target, innate immunity. Of 244 studies that were identified, 97 nonrelevant studies were excluded. In total, 147 full-text articles were assessed, and from these, 54 were excluded as they did not provide complete key information. Thus, 93 studies were considered eligible and included in the analysis. According to the data from the included trials, 14 TLR ligands (77.8%) from 82 studies have been demonstrated to display antitumor property in various cancers, whereas 4 ligands (22.2%) from 11 studies promote tumors. Among them, only 3 TLR ligands have been approved for cancer therapy, and 9 ligands were in clinical trials. In addition, the potential mechanism of recently reported targets on TLRs for clinical application was also evaluated in this review. We show that targeting TLRs in cancer immunotherapy is a promising strategy for cancer therapy, and the specific TLR ligands, either alone or combination, exhibit antitumor potential.

No MeSH data available.


Related in: MedlinePlus