Tumor-infiltrating IL-17-producing gammadelta T cells support the progression of tumor by promoting angiogenesis.
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.
Wakita
Daiko
D
Division of ROYCE' Health Bioscience, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
Sumida
Kentaro
K
Iwakura
Yoichiro
Y
Nishikawa
Hiroyoshi
H
Ohkuri
Takayuki
T
Chamoto
Kenji
K
Kitamura
Hidemitsu
H
Nishimura
Takashi
T
D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000276:immunology; D018450:Disease Progression; D020381:Interleukin-17 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000235:genetics; D054353:Perforin / Q000096:biosynthesis / Q000235:genetics; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology / Q000378:metabolism*; D012867:Skin / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D047368:Tumor Burden / Q000235:genetics
D019138:Antibodies, Blocking; D016207:Cytokines; D020381:Interleukin-17; D055655:NK Cell Lectin-Like Receptor Subfamily K; D016692:Receptors, Antigen, T-Cell, gamma-delta; D054353:Perforin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human