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

• Published in: PloS one Vol. 8; no. 1; p. e53131
• Main Authors: Hayata, Keiji, Iwahashi, Makoto, Ojima, Toshiyasu, Katsuda, Masahiro, Iida, Takeshi, Nakamori, Mikihito, Ueda, Kentaro, Nakamura, Masaki, Miyazawa, Motoki, Tsuji, Toshiaki, Yamaue, Hiroki
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 25.01.2013; Public Library of Science (PLoS)
• Subjects: Adenoviridae - genetics; Adenoviruses; Advertising executives; Analysis; Angiogenesis; Animal models; Animals; Biology; Cancer; Cancer treatment; CD8 antigen; Cell activation; Cell Line, Tumor; Cloning; Colorectal cancer; Cytokines; Cytotoxicity; Gelatinase B; Gene Expression Regulation, Neoplastic; Genetic Vectors; Immunity; Immunoregulation; Inflammation; Inhibition; Injections, Intralesional; Interleukin 17; Interleukin-17 - antagonists & inhibitors; Interleukin-17 - genetics; Interleukin-17 - immunology; Laboratory animals; Liver cancer; Lung cancer; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - pathology; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - immunology; Medical research; Medicine; Melanoma; Melanoma, Experimental - blood supply; Melanoma, Experimental - genetics; Melanoma, Experimental - metabolism; Melanoma, Experimental - pathology; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Ovarian cancer; Penicillin; Platelet Endothelial Cell Adhesion Molecule-1 - genetics; Platelet Endothelial Cell Adhesion Molecule-1 - immunology; RNA, Small Interfering - genetics; Rodents; siRNA; Skin cancer; Skin Neoplasms - blood supply; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Splenocytes; Studies; Suppressor cells; Surgery; T cells; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - pathology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - pathology; Toxicity; Tumor Microenvironment - genetics; Tumor-infiltrating lymphocytes; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - immunology; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0053131

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.