Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2014 Jul 3;33(27):3485-95.
doi: 10.1038/onc.2013.302. Epub 2013 Aug 12.

The Yin and Yang of Toll-like receptors in cancer

J-P Pradere  1 , D H Dapito  2 , R F Schwabe  2
Affiliations
Review

The Yin and Yang of Toll-like receptors in cancer

J-P Pradere et al. Oncogene. .

Abstract

Recognition of non-self molecular patterns by pattern recognition receptors is a cornerstone of innate immunity. Toll-like receptors (TLRs) exert a key role in recognizing pathogen-associated molecular patterns (PAMPs) but have also been implicated in the recognition of damage-associated molecular patterns (DAMPs). As such, TLRs regulate a wide range of biological responses including inflammatory and immune responses during carcinogenesis. The high expression of TLRs by antigen-presenting cells, including dendritic cells, and their ability to induce antitumor mediators such as type I interferon has led to efforts to utilize TLR agonists in tumor therapy in order to convert the often tolerant immune response toward antitumor responses. However, TLRs are also increasingly recognized as regulators of tumor-promoting inflammation and promoters of tumor survival signals. Here, we will review in detail the dichotomous role of TLRs in tumor biology, focusing on relevant TLR-dependent pro- and antitumor pathways, and discuss clinical applications of TLR-targeted therapies for tumor prevention and treatment.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Toll-like receptor signaling
TLRs bind bacterial and viral pathogen-associated molecular patterns (PAMPs), leading to the activation of proinflammatory and anti-viral signaling pathways including NF-κB and IRF3/IRF7, respectively. Activation of these pathways is mediated by two key adaptor molecules MyD88 and Trif. Key biological effects of NF-κB activation include prevention of apoptosis and increased inflammation. Type I interferon induces anti-viral and anti-tumor immunity.
Figure 2
Figure 2. Yin and Yang of TLRs in tumor biology
Potent activation of TLRs, in particular TLR3, TLR5, TLR7/8 and TLR9 may achieve anti-tumor effects by converting immune tolerance into anti-tumor immunity. High level TLR activation induces activation of dendritic cells (DC), which in turn activate key effect cells including natural killer (NK) cells and cytotoxic T lymphocytes (CTL) in a type I interferon-dependent manner. Moreover, DC themselves may also aquire cytotoxic and tumoricidal abilities. In addition, TRL-activated DC also inhibit Treg through IL-6 and angiogenesis through type I interferon. On the other hand, chronic low-grade stimulation of TLRs, in particular TLR2 and TLR4, leads to tumor-promoting inflammation and prevention of tumor apoptosis. This may be mediated through effects on tumor-associated macrophages (TAM), cancer-associated fibroblasts (CAF) or through direct effects in the tumor. NF-κB activation play as key role as it not only fuels inflammation but also prevent apoptosis. Finally, tumor-secreted factors, such as versican, may activate TLRs on cells of the tumor microevironment, further fueling tumor-promoting inflammatory signals.
Figure 3
Figure 3. TLR agonists for clinical anti-tumor therapies
A. Summary of trials from ClinicalTrial.gov employing TLR agonists or TLR-agonistic Bacillus Calmette-Guérin (BC). B. List of FDA-approved TLR agonists for tumor therapy (upper section) and TLR agonists currently being evaluated for tumor therapy (lower section), including the National Clinical Trial (NCT) number from ClinicalTrials.gov.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Trinchieri G. Cancer and inflammation: an old intuition with rapidly evolving new concepts. Annu Rev Immunol. 2012;30:677–706. - PubMed
    1. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357:539–545. - PubMed
    1. Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer. 2006;118:3030–3044. - PubMed
    1. Coussens LM, Zitvogel L, Palucka AK. Neutralizing tumor-promoting chronic inflammation: a magic bullet? Science. 2013;339:286–291. - PMC - PubMed
    1. Lotze MT, et al. The grateful dead: damage-associated molecular pattern molecules and reduction/oxidation regulate immunity. Immunol Rev. 2007;220:60–81. - PubMed

Publication types