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Mark A Miles1, Raymond Luong2, Eunice E To1
1Centre for Respiratory Science and Health, School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia.
Abstract:
Prostate cancer is ranked second in the world for cancer-related deaths in men, highlighting the lack of effective therapies for advanced-stage disease. Toll-like receptors (TLRs) and immunity have a direct role in prostate cancer pathogenesis, but TLR9 has been reported to contribute to both the progression and inhibition of prostate tumorigenesis. To further understand this apparent disparity, we have investigated the effect of TLR9 stimulation on prostate cancer progression in an immune-competent, syngeneic orthotopic mouse model of prostate cancer. Here, we utilized the class B synthetic agonist CPG-1668 to provoke a TLR9-mediated systemic immune response and demonstrate a significant impairment of prostate tumorigenesis. Untreated tumors contained a high abundance of immune-cell infiltrates. However, pharmacological activation of TLR9 resulted in smaller tumors containing significantly fewer M1 macrophages and T cells. TLR9 stimulation of tumor cells in vitro had no effect on cell viability or its downstream transcriptional targets, whereas stimulation in macrophages suppressed cancer cell growth via type I IFN. This suggests that the antitumorigenic effects of CPG-1668 were predominantly mediated by an antitumor immune response. This study demonstrated that systemic TLR9 stimulation negatively regulates prostate cancer tumorigenesis and highlights TLR9 agonists as a useful therapeutic for the treatment of prostate cancer.
Insights
Stimulating Toll-like receptor 9 (TLR9) with CPG-1668 impaired prostate tumor growth in mice. This suggests TLR9 agonists may offer a new therapeutic strategy for prostate cancer treatment.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Prostate cancer is a leading cause of cancer death in men, with limited effective treatments for advanced stages.
- Toll-like receptors (TLRs) play a complex role in prostate cancer, with TLR9 implicated in both tumor progression and inhibition.
- Understanding TLR9's precise role is crucial for developing novel therapeutic strategies.
Purpose of the Study:
- To investigate the effect of TLR9 stimulation on prostate cancer progression.
- To evaluate the potential of TLR9 agonists as a therapeutic agent for prostate cancer.
Main Methods:
- Utilized an immune-competent, syngeneic orthotopic mouse model of prostate cancer.
- Administered the synthetic TLR9 agonist CPG-1668 to stimulate a systemic immune response.
- Analyzed tumor size, immune cell infiltration (M1 macrophages, T cells), and tumor cell viability in vitro.
Main Results:
- Systemic TLR9 stimulation with CPG-1668 significantly impaired prostate tumorigenesis, leading to smaller tumors.
- TLR9 activation reduced the abundance of M1 macrophages and T cells within tumors.
- In vitro, TLR9 stimulation did not affect tumor cell viability but suppressed cancer cell growth when applied to macrophages via type I IFN.
Conclusions:
- Systemic TLR9 stimulation exerts an antitumorigenic effect on prostate cancer.
- The therapeutic benefits of CPG-1668 are primarily mediated by an enhanced antitumor immune response.
- TLR9 agonists represent a promising therapeutic avenue for treating prostate cancer.
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