| Simultaneous TLR2 inhibition and TLR9 activation synergistically suppress tumor metastasis in mice. | |
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MedLine Citation:
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PMID: 22426694 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Aim:To develop a rational immunotherapy against tumor metastasis by combining a Toll-like-receptor 2 (TLR2)-neutralizing antibody with a TLR9 agonist CpG ODN, and then investigate the mechanism of action for this combinational regimen.Methods:After mouse melanoma B16-F10 cell inoculation, female C57BL/6 mice were treated with either CpG ODN (0.5 mg/kg) or the anti-TLR2 antibody (200 μg/kg), or with a combination of the two agents. Pulmonary metastases were evaluated by counting metastatic nodes on the lung surface using anatomical microscopy. Flow cytometry was used to evaluate the cytotoxicity of the immune cells in tumor-draining lymph nodes, the cell population in the spleen, and the infiltration of immune cells within the lungs. Cytokine and enzyme expression in the lung tissue was evaluated using ELISA or immunostaining.Results:Anti-metastatic effects were detected in mice treated with either CpG ODN or the anti-TLR2 antibody alone. However, treatment with CpG ODN plus the anti-TLR2 antibody synergistically suppressed the metastasis as compared with treatment with either single agent. The combinational treatment resulted in enhanced infiltration of natural killer cells and cytotoxic T cells, reduced recruitment of type 2 macrophages and Tregs, and decreased expression of immunosuppressive factors including TGF-β1, cyclooxygenase-2 and indoleamine 2,3-dioxygenase, thus stimulated tumor cytotoxicity and suppressed metastasis. The anti-metastatic effect of the combinational regimen was further confirmed in spontaneous metastatic mouse model of Lewis lung carcinoma.Conclusion:Our studies suggest that combining a TLR9 agonist with an anti-TLR2 antibody, which eliminates immunosuppressive factors from the tumor environment, is critical for an effective anti-metastatic immunotherapy. |
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Authors:
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Jun Yan; Fang Hua; Han-Zhi Liu; Hong-Zheng Yang; Zhuo-Wei Hu |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-3-19 |
Journal Detail:
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Title: Acta pharmacologica Sinica Volume: - ISSN: 1745-7254 ISO Abbreviation: - Publication Date: 2012 Mar |
Date Detail:
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Created Date: 2012-3-19 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100956087 Medline TA: Acta Pharmacol Sin Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Molecular Immunology and Pharmacology Laboratory State Key Laboratory of Bioactive Substance and Function of Natural Medicines; Institute of Meteria Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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