Open Access

A matrix metalloproteinase inhibitor enhances anti-cytotoxic T lymphocyte antigen-4 antibody immunotherapy in breast cancer by reprogramming the tumor microenvironment

  • Authors:
    • Mingyue Li
    • Shugang Xing
    • Haiying Zhang
    • Siqi Shang
    • Xiangxiang Li
    • Bo Ren
    • Gaiyun Li
    • Xiaona Chang
    • Yilei Li
    • Wei Li
  • View Affiliations

  • Published online on: January 5, 2016     https://doi.org/10.3892/or.2016.4547
  • Pages: 1329-1339
  • Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) treatment is effective for the treatment of primary tumors, but not sufficient for the treatment of metastatic tumors, likely owing to the effects of the tumor microenvironment. In this study, we aimed to determine the therapeutic effects of combined treatment with a matrix metalloproteinase (MMP) inhibitor (MMPI) and anti-CTLA-4 antibody in a breast cancer model in mice. Interestingly, combined treatment with MMPI and anti-CTLA-4 antibody delayed tumor growth and reduced lung and liver metastases compared with anti-CTLA-4 alone or vehicle treatment. The functions of the liver and kidney in mice in the different groups did not differ significantly compared with that in normal mice. The CD8+/CD4+ ratio in T cells in the spleen and tumor were increased after monotherapy or combined anti-CTLA-4 antibody plus MMPI therapy compared with that in vehicle-treated mice. Anti-CTLA-4 antibody plus MMPI therapy reduced the percentage of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) and decreased the Treg/Th17 cell ratio in the spleen compared with those in the vehicle-treated group. Additionally, anti-CTLA-4 antibody plus MMPI therapy reduced the percentages of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and Th17 cells in tumors compared with that in the vehicle-treated group. Moreover, combined treatment with MMPI and anti-CTLA-4 antibody reduced the microvessel density (MVD) in tumors compared with that in vehicle or MMPI-treated mice. There was a negative correlation between MVD and the CD8+ T cell percentage, CD4+ T cell percentage, and CD8+/CD4+ T cell ratio, but a positive correlation with Tregs, Th17 cells, Treg/Th17 cell ratio, and MDSCs. Thus, these data demonstrated that addition of MMPI enhanced the effects of anti-CTLA-4 antibody treatment in a mouse model of breast cancer by delaying tumor growth and reducing metastases.
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March-2016
Volume 35 Issue 3

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Li M, Xing S, Zhang H, Shang S, Li X, Ren B, Li G, Chang X, Li Y, Li W, Li W, et al: A matrix metalloproteinase inhibitor enhances anti-cytotoxic T lymphocyte antigen-4 antibody immunotherapy in breast cancer by reprogramming the tumor microenvironment. Oncol Rep 35: 1329-1339, 2016
APA
Li, M., Xing, S., Zhang, H., Shang, S., Li, X., Ren, B. ... Li, W. (2016). A matrix metalloproteinase inhibitor enhances anti-cytotoxic T lymphocyte antigen-4 antibody immunotherapy in breast cancer by reprogramming the tumor microenvironment. Oncology Reports, 35, 1329-1339. https://doi.org/10.3892/or.2016.4547
MLA
Li, M., Xing, S., Zhang, H., Shang, S., Li, X., Ren, B., Li, G., Chang, X., Li, Y., Li, W."A matrix metalloproteinase inhibitor enhances anti-cytotoxic T lymphocyte antigen-4 antibody immunotherapy in breast cancer by reprogramming the tumor microenvironment". Oncology Reports 35.3 (2016): 1329-1339.
Chicago
Li, M., Xing, S., Zhang, H., Shang, S., Li, X., Ren, B., Li, G., Chang, X., Li, Y., Li, W."A matrix metalloproteinase inhibitor enhances anti-cytotoxic T lymphocyte antigen-4 antibody immunotherapy in breast cancer by reprogramming the tumor microenvironment". Oncology Reports 35, no. 3 (2016): 1329-1339. https://doi.org/10.3892/or.2016.4547