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Inhibition of IL-17A in tumor microenvironment augments cytotoxicity of tumor-infiltrating lymphocytes in tumor-bearing mice.

Abstract
It remains controversial whether IL-17A promotes or inhibits cancer progression. We hypothesized that IL-17A that is locally produced in the tumor microenvironment has an important role in angiogenesis and tumor immunity. We investigated the effect of inhibiting IL-17A at tumor sites on tumor growth and on local and systemic anti-tumor immunity. MC38 or B16 cells were inoculated subcutaneously into mice, and intratumoral injection of an adenovirus vector expressing siRNA against the mouse IL-17A gene (Ad-si-IL-17) significantly inhibited tumor growth in both tumor models compared with control mice. Inhibition of IL-17A at tumor sites significantly suppressed CD31, MMP9, and VEGF expression in tumor tissue. The cytotoxic activity of CD8(+) T cells from tumor-infiltrating lymphocytes in mice treated with Ad-si-IL-17 was significantly higher than in control mice; however, CD8(+) T cells from splenocytes had similar activity levels. Suppression of IL-17A at tumor sites led to a Th1-dominant environment, and moreover, eliminated myeloid-derived suppressor cells and regulatory T cells at tumor sites but not in splenocytes. In conclusion, blockade of IL-17A at tumor sites helped suppress tumor growth by inhibiting angiogenesis as well as cytotoxic T lymphocytes activation at tumor sites.
AuthorsKeiji Hayata, Makoto Iwahashi, Toshiyasu Ojima, Masahiro Katsuda, Takeshi Iida, Mikihito Nakamori, Kentaro Ueda, Masaki Nakamura, Motoki Miyazawa, Toshiaki Tsuji, Hiroki Yamaue
JournalPloS one (PLoS One) Vol. 8 Issue 1 Pg. e53131 ( 2013) ISSN: 1932-6203 [Electronic] United States
PMID23372655 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antigens, CD31
  • Interleukin-17
  • RNA, Small Interfering
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Mmp9 protein, mouse
  • Matrix Metalloproteinase 9
Topics
  • Adenoviridae (genetics)
  • Animals
  • Antigens, CD31 (genetics, immunology)
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic
  • Genetic Vectors
  • Injections, Intralesional
  • Interleukin-17 (antagonists & inhibitors, genetics, immunology)
  • Lymphocytes, Tumor-Infiltrating (immunology, pathology)
  • Matrix Metalloproteinase 9 (genetics, immunology)
  • Melanoma, Experimental (blood supply, genetics, metabolism, pathology)
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Pathologic
  • RNA, Small Interfering (genetics)
  • Skin Neoplasms (blood supply, genetics, metabolism, pathology)
  • T-Lymphocytes, Cytotoxic (immunology, pathology)
  • T-Lymphocytes, Regulatory (immunology, pathology)
  • Tumor Microenvironment (genetics)
  • Vascular Endothelial Growth Factor A (genetics, immunology)

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