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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

Relation of TLRs on immune cells and tumor cells to tumor immunotherapy is depicted. (A) TLRs of immune cells act as sensors in immune surveillance. (B) Sufficient immune cells recognize tumor antigens by TLRs and cause cell destruction through cell lysis, phagocytosis of dying cell, and cytokines secretion. (C) TLRs on tumor cells display different roles in the malignant process. Some TLRs on tumor cells facilitate immune escape, whereas other TLRs could terminate tolerant immune system and induce strong antitumor effects. TLRs = toll-like receptors.
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Figure 1: Relation of TLRs on immune cells and tumor cells to tumor immunotherapy is depicted. (A) TLRs of immune cells act as sensors in immune surveillance. (B) Sufficient immune cells recognize tumor antigens by TLRs and cause cell destruction through cell lysis, phagocytosis of dying cell, and cytokines secretion. (C) TLRs on tumor cells display different roles in the malignant process. Some TLRs on tumor cells facilitate immune escape, whereas other TLRs could terminate tolerant immune system and induce strong antitumor effects. TLRs = toll-like receptors.

Mentions: TLRs of immune cells serve as sensors in immune surveillance. Immune cells recognize tumor antigens by TLRs, and infiltrate tumor stroma, which cause tumor destruction by direct lysis or cytokines secretion.[42] However, TLRs on tumor cells may facilitate immune escape of tumor.[43–45] Recent studies manifest different functions of TLRs on tumor cells. Activated TLRs in malignant process may play opposite roles: TLR signaling may promote cancer metastasis or kill tumor cells. Certain TLRs have been demonstrated to induce strong antitumor effects,[46] and TLR signaling has been shown to enhance DC maturation and antigen presentation, which is one of the key issues in the effective tumor therapy. Some TLRs on tumor cells and immune cells have been considered as potential targets for antitumor immunotherapy to terminate tolerant immune system and kill tumor cells (Fig. 1). Thus, the potential of TLR agonists, as anticancer agents or vaccines, to induce effective immune reactions against tumor antigens has been exploited. Coley toxin (mixture of killed Streptococcus pyogenes and Serratia marcescens bacteria) and bacillus Calmette–Guerin (BCG) have become long-used anticancer drugs, which potently activate TLR2 and TLR4 signaling.[47] TLR2 and TLR4 agonist, extract of larix leptolepis (ELL), activates bone marrow-derived dendritic cells (BMDCs) to induce the production of cytokines IL-12 and TNF-а, and induces tumor-specific cytotoxic T lymphocytes (CTLs) against cancer.[48] TLR2 ligand HP-NAP (Helicobacter pylori neutrophil activating protein) is a potential therapeutic agent for nonmuscle invasive bladder cancer. HP-NAP is able to enhance the induction of the T helper 1 (TH1) cell differentiation and reduce vascularization of cancer through induction of IFN-γ.[49] Lin et al found that TLR2 signaling in carcinogen diethylnitrosamine (DEN)-injured liver tissue induced intracellular senescence and activated autophagy to eliminate ROS accumulation and DNA damage, therefore, attenuated the development and progression of HCC. Accordingly, loss of TLR2 increased the susceptibility to DEN-induced hepatocellular carcinogenesis.[50,51]


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

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

Relation of TLRs on immune cells and tumor cells to tumor immunotherapy is depicted. (A) TLRs of immune cells act as sensors in immune surveillance. (B) Sufficient immune cells recognize tumor antigens by TLRs and cause cell destruction through cell lysis, phagocytosis of dying cell, and cytokines secretion. (C) TLRs on tumor cells display different roles in the malignant process. Some TLRs on tumor cells facilitate immune escape, whereas other TLRs could terminate tolerant immune system and induce strong antitumor effects. TLRs = toll-like receptors.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Relation of TLRs on immune cells and tumor cells to tumor immunotherapy is depicted. (A) TLRs of immune cells act as sensors in immune surveillance. (B) Sufficient immune cells recognize tumor antigens by TLRs and cause cell destruction through cell lysis, phagocytosis of dying cell, and cytokines secretion. (C) TLRs on tumor cells display different roles in the malignant process. Some TLRs on tumor cells facilitate immune escape, whereas other TLRs could terminate tolerant immune system and induce strong antitumor effects. TLRs = toll-like receptors.
Mentions: TLRs of immune cells serve as sensors in immune surveillance. Immune cells recognize tumor antigens by TLRs, and infiltrate tumor stroma, which cause tumor destruction by direct lysis or cytokines secretion.[42] However, TLRs on tumor cells may facilitate immune escape of tumor.[43–45] Recent studies manifest different functions of TLRs on tumor cells. Activated TLRs in malignant process may play opposite roles: TLR signaling may promote cancer metastasis or kill tumor cells. Certain TLRs have been demonstrated to induce strong antitumor effects,[46] and TLR signaling has been shown to enhance DC maturation and antigen presentation, which is one of the key issues in the effective tumor therapy. Some TLRs on tumor cells and immune cells have been considered as potential targets for antitumor immunotherapy to terminate tolerant immune system and kill tumor cells (Fig. 1). Thus, the potential of TLR agonists, as anticancer agents or vaccines, to induce effective immune reactions against tumor antigens has been exploited. Coley toxin (mixture of killed Streptococcus pyogenes and Serratia marcescens bacteria) and bacillus Calmette–Guerin (BCG) have become long-used anticancer drugs, which potently activate TLR2 and TLR4 signaling.[47] TLR2 and TLR4 agonist, extract of larix leptolepis (ELL), activates bone marrow-derived dendritic cells (BMDCs) to induce the production of cytokines IL-12 and TNF-а, and induces tumor-specific cytotoxic T lymphocytes (CTLs) against cancer.[48] TLR2 ligand HP-NAP (Helicobacter pylori neutrophil activating protein) is a potential therapeutic agent for nonmuscle invasive bladder cancer. HP-NAP is able to enhance the induction of the T helper 1 (TH1) cell differentiation and reduce vascularization of cancer through induction of IFN-γ.[49] Lin et al found that TLR2 signaling in carcinogen diethylnitrosamine (DEN)-injured liver tissue induced intracellular senescence and activated autophagy to eliminate ROS accumulation and DNA damage, therefore, attenuated the development and progression of HCC. Accordingly, loss of TLR2 increased the susceptibility to DEN-induced hepatocellular carcinogenesis.[50,51]

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