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Tumor-infiltrating IL-17-producing gammadelta T cells support the progression of tumor by promoting angiogenesis.

Abstract
Based on the evidence that IL-17 is a key cytokine involved in various inflammatory diseases, we explored the critical role of IL-17-producing gammadelta T cells for tumor development in tumor-bearing mouse model. IL-17(-/-) mice exhibited a significant reduction of tumor growth, concomitantly with the decrease of vascular density at lesion area, indicating a pro-tumor property of IL-17. Among tumor-infiltrating lymphocytes (TIL), gammadelta T cells were the major cellular source of IL-17. Analysis of TCR repertoires in TIL-gammadelta T cells showed that circulating gammadelta T cells, but not skin resident Vgamma5(+)gammadelta T cells, produced IL-17. Neutralizing antibodies against IL-23, IL-6, and TGF-beta, which were produced within the tumor microenvironment, inhibited the induction of IL-17-producing gammadelta T cells. IL-17 production by tumor-infiltrating gammadelta T cells was blocked by anti-gammadeltaTCR or anti-NKG2D antibodies, indicating that these ligands, expressed within the tumor microenvironment, are involved in gammadelta T-cell activation. The IL-17-producing TIL-gammadelta T cells exhibited reduced levels of perforin mRNA expression, but increased levels of COX-2 mRNA expression. Together, our findings support the novel concept that IL-17-producing gammadelta T cells, generated in response to tumor microenvironment, act as tumor-promoting cells by inducing angiogenesis.
AuthorsDaiko Wakita, Kentaro Sumida, Yoichiro Iwakura, Hiroyoshi Nishikawa, Takayuki Ohkuri, Kenji Chamoto, Hidemitsu Kitamura, Takashi Nishimura
JournalEuropean journal of immunology (Eur J Immunol) Vol. 40 Issue 7 Pg. 1927-37 (Jul 2010) ISSN: 1521-4141 [Electronic] Germany
PMID20397212 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antibodies, Blocking
  • Cytokines
  • Interleukin-17
  • NK Cell Lectin-Like Receptor Subfamily K
  • Receptors, Antigen, T-Cell, gamma-delta
  • Perforin
  • Cyclooxygenase 2
  • PTGS2 protein, human
Topics
  • Animals
  • Antibodies, Blocking (administration & dosage)
  • Cell Line, Tumor
  • Cyclooxygenase 2 (biosynthesis, genetics)
  • Cytokines (immunology)
  • Disease Progression
  • Interleukin-17 (biosynthesis, genetics, immunology, secretion)
  • Lymphocyte Activation (drug effects, genetics)
  • Lymphocytes, Tumor-Infiltrating (drug effects, immunology, metabolism, pathology)
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • NK Cell Lectin-Like Receptor Subfamily K (immunology)
  • Neoplasm Transplantation
  • Neoplasms, Experimental (blood supply, immunology, pathology, physiopathology)
  • Neovascularization, Pathologic (genetics)
  • Perforin (biosynthesis, genetics)
  • Receptors, Antigen, T-Cell, gamma-delta (immunology, metabolism)
  • Skin (pathology)
  • T-Lymphocytes (drug effects, immunology, metabolism, pathology)
  • Tumor Burden (genetics)

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