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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cancer Vaccines
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Carcinoma, Lewis Lung / immunology
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Carcinoma, Lewis Lung / pathology
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Disease Progression
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Gene Expression Profiling
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Homeodomain Proteins / genetics
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Humans
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Immunotherapy, Adoptive
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Interleukin-9 / analysis
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Interleukin-9 / biosynthesis*
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Interleukin-9 / genetics
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Interleukin-9 / physiology
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Lymphatic Metastasis
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Lymphocytes, Tumor-Infiltrating / immunology
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Mast Cells / drug effects
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Mast Cells / immunology
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Melanoma / chemistry
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Melanoma / immunology*
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Melanoma / pathology
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Melanoma / secondary
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Melanoma, Experimental / immunology
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Melanoma, Experimental / pathology
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Melanoma, Experimental / therapy
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Neoplasm Proteins / analysis
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Nuclear Receptor Subfamily 1, Group F, Member 3 / deficiency
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Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
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Radiation Chimera
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Receptors, Interleukin / deficiency
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Receptors, Interleukin / genetics
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Recombinant Fusion Proteins / physiology
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Skin / immunology
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Skin Neoplasms / chemistry
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Skin Neoplasms / immunology*
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Skin Neoplasms / pathology
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism
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Tumor Burden
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Vaccination
Substances
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Cancer Vaccines
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Homeodomain Proteins
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IL9 protein, human
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Interleukin-9
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Neoplasm Proteins
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Nuclear Receptor Subfamily 1, Group F, Member 3
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Receptors, Interleukin
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Recombinant Fusion Proteins
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Rorc protein, mouse
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interleukin-23 receptor, mouse
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RAG-1 protein