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.

• Authors: Keiji Hayata, Makoto Iwahashi, Toshiyasu Ojima, Masahiro Katsuda, Takeshi Iida, Mikihito Nakamori, Kentaro Ueda, Masaki Nakamura, Motoki Miyazawa, Toshiaki Tsuji, Hiroki Yamaue
• Journal: PloS one (PLoS One) Vol. 8 Issue 1 Pg. e53131 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23372655 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-17
• Platelet Endothelial Cell Adhesion Molecule-1
• RNA, Small Interfering
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, mouse
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse

Topics

• Adenoviridae (genetics)
• Animals
• 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
• Platelet Endothelial Cell Adhesion Molecule-1 (genetics, immunology)
• 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)