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Toll-like receptors in urothelial cells—targets for cancer immunotherapy

Nature Reviews Urology volume 10, pages 537–545 (2013)Cite this article

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Abstract

Toll-like receptors (TLRs) have an important role in the activation of both innate and adaptive immunity in response to pathogens and danger signals. These receptors are expressed in immune cells and in some epithelia. They are expressed in the epithelium of the urinary bladder, where they actively participate in the fight against infection by uropathogens. TLR expression is decreased (although still evident) in bladder tumours, especially in non-muscle-invasive tumours. Intravesical immunotherapy with BCG to prevent recurrence of these tumours has been shown to involve the participation of three different TLRs (TLR2, TLR4, and TLR9). However, alternative therapies are needed as BCG fails in some patients and can sometimes cause severe adverse effects that are difficult to tolerate. In recent years, TLR2, TLR4, TLR7, and TLR9 agonists have been tested in vitro and in vivo for their ability to activate an antitumour immune response against bladder cancer. Promising results from these studies have led to the testing of TLR7 and TLR9 agonists in clinical trials.

Key Points

  • Toll-like receptors (TLRs) are transmembrane proteins present in immune cells and some epithelial cells, which initiate an immune response upon activation by microbial pathogens or danger signals

  • TLRs are expressed and active in normal bladder epithelial cells, where they contribute to resistance against infection by uropathogens

  • Expression of TLRs is maintained, although slightly reduced, in non-muscle-invasive bladder cancer cells compared with normal bladder epithelial cells

  • TLR agonists can be used to activate TLR pathways and some have been used successfully to treat various diseases, including some cancers (for example, basal cell carcinomas)

  • TLR agonists have been tested for their ability to treat bladder cancer in vitro and in vivo using animal models, with promising results

  • Some TLR agonists, such as mycobacterial cell wall DNA complexes and imiquimod, have been tested in clinical trials on patients with bladder cancer

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Figure 1: Simplified representation of the TLR response to uropathogens and to BCG in the human bladder.
Figure 2: Reverse transcriptase PCR analysis of TLR mRNA expression in four short-term primary cultures of normal human urothelial cells and 15 bladder cancer cell lines.

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Authors and Affiliations

  1. Centre de Recherche en Cancérologie de l'Université Laval, CHU de Québec-L'Hôtel-Dieu de Québec, 10 McMahon, Québec, G1R 3S1, QC, Canada

    Hélène LaRue, Cherifa Ayari, Alain Bergeron & Yves Fradet

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  1. Hélène LaRue
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  2. Cherifa Ayari
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  3. Alain Bergeron
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  4. Yves Fradet
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H. LaRue, C. Ayari, and A. Bergeron researched, wrote, edited, and discussed this Review article. Y. Fradet made substantial contributions towards discussions of contents and reviewed the manuscript before submission.

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Correspondence to Yves Fradet.

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The authors declare no competing financial interests.

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LaRue, H., Ayari, C., Bergeron, A. et al. Toll-like receptors in urothelial cells—targets for cancer immunotherapy. Nat Rev Urol 10, 537–545 (2013). https://doi.org/10.1038/nrurol.2013.153

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