title: Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells.
abstract: Interleukin-9 (IL-9) is a T cell cytokine that acts through a γC-family receptor on target cells and is associated with inflammation and allergy. We determined that T cells from mice deficient in the T helper type 17 (T(H)17) pathway genes encoding retinoid-related orphan receptor γ (ROR-γ) and IL-23 receptor (IL-23R) produced abundant IL-9, and we found substantial growth inhibition of B16F10 melanoma in these mice. IL-9-blocking antibodies reversed this tumor growth inhibition and enhanced tumor growth in wild-type (WT) mice. Il9r(-/-) mice showed accelerated tumor growth, and administration of recombinant IL-9 (rIL-9) to tumor-bearing WT and Rag1(-/-) mice inhibited melanoma as well as lung carcinoma growth. Adoptive transfer of tumor-antigen-specific T(H)9 cells into both WT and Rag1(-/-) mice suppressed melanoma growth; this effect was abrogated by treatment with neutralizing antibodies to IL-9. Exogenous rIL-9 inhibited tumor growth in Rag1(-/-) mice but not in mast-cell-deficient mice, suggesting that the targets of IL-9 in this setting include mast cells but not T or B cells. In addition, we found higher numbers of T(H)9 cells in normal human skin and blood compared to metastatic lesions of subjects with progressive stage IV melanoma. These results suggest a role for IL-9 in tumor immunity and offer insight into potential therapeutic strategies.
authors: Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: Rahul
authors: R
authors: Purwar
authors: Christoph
authors: C
authors: Schlapbach
authors: Sheng
authors: S
authors: Xiao
authors: Hong Soon
authors: HS
authors: Kang
authors: Wassim
authors: W
authors: Elyaman
authors: Xiaodong
authors: X
authors: Jiang
authors: Anton M
authors: AM
authors: Jetten
authors: Samia J
authors: SJ
authors: Khoury
authors: Robert C
authors: RC
authors: Fuhlbrigge
authors: Vijay K
authors: VK
authors: Kuchroo
authors: Rachael A
authors: RA
authors: Clark
authors: Thomas S
authors: TS
authors: Kupper
mesh_terms: D000818:Animals; D019496:Cancer Vaccines; D018827:Carcinoma, Lewis Lung / Q000276:immunology / Q000473:pathology; D018450:Disease Progression; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D016219:Immunotherapy, Adoptive; D016906:Interleukin-9 / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D008207:Lymphatic Metastasis; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology; D008545:Melanoma / Q000737:chemistry / Q000276:immunology* / Q000473:pathology / Q000556:secondary; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000172:deficiency / Q000235:genetics; D011828:Radiation Chimera; D018123:Receptors, Interleukin / Q000172:deficiency / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012867:Skin / Q000276:immunology; D012878:Skin Neoplasms / Q000737:chemistry / Q000276:immunology* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D047368:Tumor Burden; D014611:Vaccination
chemical_list: D019496:Cancer Vaccines; D018398:Homeodomain Proteins; C508607:IL9 protein, human; D016906:Interleukin-9; D009363:Neoplasm Proteins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D018123:Receptors, Interleukin; D011993:Recombinant Fusion Proteins; C539901:Rorc protein, mouse; C528688:interleukin-23 receptor, mouse; C064658:RAG-1 protein