Inhibition of IL-17A in tumor microenvironment augments cytotoxicity of tumor-infiltrating lymphocytes in tumor-bearing mice.
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.
Second Department of Surgery, School of Medicine, Wakayama Medical University, Wakayama, Japan.
Keiji
K
Hayata
Makoto
M
Iwahashi
Toshiyasu
T
Ojima
Masahiro
M
Katsuda
Takeshi
T
Iida
Mikihito
M
Nakamori
Kentaro
K
Ueda
Masaki
M
Nakamura
Motoki
M
Miyazawa
Toshiaki
T
Tsuji
Hiroki
H
Yamaue
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors; D015552:Injections, Intralesional; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000276:immunology; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology; D034741:RNA, Small Interfering / Q000235:genetics; D012878:Skin Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology; D059016:Tumor Microenvironment / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000276:immunology
D020381:Interleukin-17; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse