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A Natural CCR2 Antagonist Relieves Tumor-associated Macrophage-mediated Immunosuppression to Produce a Therapeutic Effect for Liver Cancer.

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  • Additional Information
    • Source:
      Publisher: Elsevier B.V Country of Publication: Netherlands NLM ID: 101647039 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2352-3964 (Electronic) Linking ISSN: 23523964 NLM ISO Abbreviation: EBioMedicine Subsets: MEDLINE
    • Publication Information:
      Original Publication: [Amsterdam] : Elsevier B.V., [2014]-
    • Subject Terms:
    • Abstract:
      Hepatocellular carcinoma (HCC) is a common malignant tumor in the digestive tract with limited therapeutic choices. Although sorafenib, an orally administered multikinase inhibitor, has produced survival benefits for patients with advanced HCC, favorable clinical outcomes are limited due to individual differences and resistance. The application of immunotherapy, a promising approach for HCC is urgently needed. Macrophage infiltration, mediated by the CCL2/CCR2 axis, is a potential immunotherapeutic target. Here, we report that a natural product from Abies georgei, named 747 and related in structure to kaempferol, exhibits sensitivity and selectivity as a CCR2 antagonist. The specificity of 747 on CCR2 was demonstrated via calcium flux, the binding domain of CCR2 was identified in an extracellular loop by chimera binding assay, and in vivo antagonistic activity of 747 was confirmed through a thioglycollate-induced peritonitis model. In animals, 747 elevated the number of CD8+ T cells in tumors via blocking tumor-infiltrating macrophage-mediated immunosuppression and inhibited orthotopic and subcutaneous tumor growth in a CD8+ T cell-dependent manner. Further, 747 enhanced the therapeutic efficacy of low-dose sorafenib without obvious toxicity, through elevating the numbers of intra-tumoral CD8+ T cells and increasing death of tumor cells. Thus, we have discovered a natural CCR2 antagonist and have provided a new perspective on development of this antagonist for treatment of HCC. In mouse models of HCC, 747 enhanced the tumor immunosuppressive microenvironment and potentiated the therapeutic effect of sorafenib, indicating that the combination of an immunomodulator with a chemotherapeutic drug could be a new approach for treating HCC.
      (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)
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    • Contributed Indexing:
      Keywords: Combination therapy; Experimental therapeutics; Immunotherapy; Kaempferol; Preclinical models
    • Accession Number:
      0 (CCR2 protein, human)
      0 (Phenylurea Compounds)
      0 (Plant Extracts)
      0 (Receptors, CCR2)
      25X51I8RD4 (Niacinamide)
      9ZOQ3TZI87 (Sorafenib)
    • Publication Date:
      Date Created: 20170730 Date Completed: 20180131 Latest Revision: 20181202
    • Publication Date:
      20201019
    • Accession Number:
      PMC5552238
    • Accession Number:
      10.1016/j.ebiom.2017.07.014
    • Accession Number:
      28754304
  • Citations
    • ABNT:
      YAO, W. et al. A Natural CCR2 Antagonist Relieves Tumor-associated Macrophage-mediated Immunosuppression to Produce a Therapeutic Effect for Liver Cancer. EBioMedicine, [s. l.], v. 22, p. 58–67, 2017. DOI 10.1016/j.ebiom.2017.07.014. Disponível em: http://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=mdc&AN=28754304. Acesso em: 28 out. 2020.
    • AMA:
      Yao W, Ba Q, Li X, et al. A Natural CCR2 Antagonist Relieves Tumor-associated Macrophage-mediated Immunosuppression to Produce a Therapeutic Effect for Liver Cancer. EBioMedicine. 2017;22:58-67. doi:10.1016/j.ebiom.2017.07.014
    • APA:
      Yao, W., Ba, Q., Li, X., Li, H., Zhang, S., Yuan, Y., Wang, F., Duan, X., Li, J., Zhang, W., & Wang, H. (2017). A Natural CCR2 Antagonist Relieves Tumor-associated Macrophage-mediated Immunosuppression to Produce a Therapeutic Effect for Liver Cancer. EBioMedicine, 22, 58–67. https://doi.org/10.1016/j.ebiom.2017.07.014
    • Chicago/Turabian: Author-Date:
      Yao, Wenbo, Qian Ba, Xiaoguang Li, Huiliang Li, Shoude Zhang, Ya Yuan, Feng Wang, et al. 2017. “A Natural CCR2 Antagonist Relieves Tumor-Associated Macrophage-Mediated Immunosuppression to Produce a Therapeutic Effect for Liver Cancer.” EBioMedicine 22 (August): 58–67. doi:10.1016/j.ebiom.2017.07.014.
    • Harvard:
      Yao, W. et al. (2017) ‘A Natural CCR2 Antagonist Relieves Tumor-associated Macrophage-mediated Immunosuppression to Produce a Therapeutic Effect for Liver Cancer’, EBioMedicine, 22, pp. 58–67. doi: 10.1016/j.ebiom.2017.07.014.
    • Harvard: Australian:
      Yao, W, Ba, Q, Li, X, Li, H, Zhang, S, Yuan, Y, Wang, F, Duan, X, Li, J, Zhang, W & Wang, H 2017, ‘A Natural CCR2 Antagonist Relieves Tumor-associated Macrophage-mediated Immunosuppression to Produce a Therapeutic Effect for Liver Cancer’, EBioMedicine, vol. 22, pp. 58–67, viewed 28 October 2020, .
    • MLA:
      Yao, Wenbo, et al. “A Natural CCR2 Antagonist Relieves Tumor-Associated Macrophage-Mediated Immunosuppression to Produce a Therapeutic Effect for Liver Cancer.” EBioMedicine, vol. 22, Aug. 2017, pp. 58–67. EBSCOhost, doi:10.1016/j.ebiom.2017.07.014.
    • Chicago/Turabian: Humanities:
      Yao, Wenbo, Qian Ba, Xiaoguang Li, Huiliang Li, Shoude Zhang, Ya Yuan, Feng Wang, et al. “A Natural CCR2 Antagonist Relieves Tumor-Associated Macrophage-Mediated Immunosuppression to Produce a Therapeutic Effect for Liver Cancer.” EBioMedicine 22 (August 2017): 58–67. doi:10.1016/j.ebiom.2017.07.014.
    • Vancouver/ICMJE:
      Yao W, Ba Q, Li X, Li H, Zhang S, Yuan Y, et al. A Natural CCR2 Antagonist Relieves Tumor-associated Macrophage-mediated Immunosuppression to Produce a Therapeutic Effect for Liver Cancer. EBioMedicine [Internet]. 2017 Aug [cited 2020 Oct 28];22:58–67. Available from: http://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=mdc&AN=28754304