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Inhibition of TLR7 and TLR9 Reduces Human Cholangiocarcinoma Cell Proliferation and Tumor Development
Fatma El Zahraa Mohamed1,2, Rajiv Jalan1, Shane Minogue1
1UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK.
Background:
Toll-like receptors (TLRs) are key players in innate immunity and modulation of TLR signaling has been demonstrated to profoundly affect proliferation and growth in different types of cancer. However, the role of TLRs in human intrahepatic cholangiocarcinoma (ICC) pathogenesis remains largely unexplored.
Aims:
We set out to determine if TLRs play any role in ICCs which could potentially make them useful treatment targets.
Methods:
Tissue microarrays containing samples from 9 human ICCs and normal livers were examined immunohistochemically for TLR4, TLR7, and TLR9 expression. Proliferation of human ICC cell line HuCCT1 was measured by MTS assay following treatment with CpG-ODN (TLR9 agonist), imiquimod (TLR7 agonist), chloroquine (TLR7 and TLR9 inhibitor) and IRS-954 (TLR7 and TLR9 antagonist). The in vivo effects of CQ and IRS-954 on tumor development were also examined in a NOD-SCID mouse xenograft model of human ICC.
Results:
TLR4 was expressed in all normal human bile duct epithelium but absent in the majority (60%) of ICCs. TLR7 and TLR9 were expressed in 80% of human ICCs. However, TLR7 was absent in all cases of normal human bile duct epithelium and only one was TLR9 positive. HuCCT1 cell proliferation in vitro significantly increased following IMQ or CpG-ODN treatment (P < 0.03 and P < 0.002, respectively) but decreased with CQ (P < 0.02). In the mouse xenograft model there was significant reduction in size of tumors from CQ and IRS-954 treated mice compared to untreated controls.
Conclusion:
TLR7 and TLR9 should be further explored for their potential as actionable targets in the treatment of ICC.
Insights
Toll-like receptors 7 and 9 (TLR7 and TLR9) are expressed in intrahepatic cholangiocarcinoma (ICC) and may serve as therapeutic targets. Inhibiting these TLRs reduced ICC cell proliferation and tumor growth in preclinical models.
Area of Science:
- Immunology
- Oncology
- Gastroenterology
Background:
- Toll-like receptors (TLRs) are crucial in innate immunity, influencing cancer cell proliferation and growth.
- The specific role of TLRs in the pathogenesis of human intrahepatic cholangiocarcinoma (ICC) is not well understood.
Purpose of the Study:
- To investigate the expression and role of TLRs in human ICC.
- To evaluate TLRs as potential therapeutic targets for ICC treatment.
Main Methods:
- Immunohistochemical analysis of TLR4, TLR7, and TLR9 expression in human ICC and normal liver tissues.
- In vitro proliferation assays of ICC cell lines treated with TLR agonists and antagonists.
- In vivo xenograft mouse models to assess the effect of TLR inhibitors on tumor development.
Main Results:
- TLR4 was downregulated in ICC compared to normal bile ducts.
- TLR7 and TLR9 were significantly expressed in ICC but not in normal bile ducts.
- TLR7 and TLR9 agonists increased ICC cell proliferation, while inhibitors decreased it and reduced tumor growth in vivo.
Conclusions:
- TLR7 and TLR9 are upregulated in ICC and promote tumor cell proliferation.
- Targeting TLR7 and TLR9 presents a promising therapeutic strategy for intrahepatic cholangiocarcinoma.
