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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 ?C-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 ? (ROR-?) 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.

SUBMITTER: Purwar R

PROVIDER: S-EPMC3518666 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells.

Purwar Rahul R Schlapbach Christoph C Xiao Sheng S Kang Hong Soon HS Elyaman Wassim W Jiang Xiaodong X Jetten Anton M AM Khoury Samia J SJ Fuhlbrigge Robert C RC Kuchroo Vijay K VK Clark Rachael A RA Kupper Thomas S TS

Nature medicine 20120708 8

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 tum ...[more]

PMID: 22772464

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Project description:BackgroundIncreased frequency of CCR9+ CD4+ T cells in peripheral blood is linked to several gastrointestinal inflammatory diseases; however, its relationship with necrotizing enterocolitis (NEC) is not understood. We investigated whether the frequencies of CCR9+ CD4+ T cells and related subsets were increased in peripheral blood of both patients and mice with NEC.MethodsCCR9+ CD4+ T cells and related subsets were evaluated by flow cytometry in peripheral blood collected from both patients and mice with NEC and controls. The suppressive function of CCR9+ regulatory T (Treg) cells in NEC was assessed via in vitro suppression assay. An in vitro T cell polarization assay was performed to investigate the role of proinflammatory cytokines in Treg cell polarization. In vivo Treg cell polarization analysis was performed using NEC mice treated with anti-interleukin-6 (IL-6) receptor antibody.FindingsA higher proportion of CCR9+ CD4+ T cells occurred in peripheral blood of both patients and mice with NEC than in controls. Elevated CCR9+ CD4+ T cells were primarily CCR9+ IL-17-producing Treg cells, possessing features of conventional Treg cells, but their suppressive activity was seriously impaired and negatively correlated with the severity of intestinal tissue injury. IL-6 promoted polarization of CCR9+ Treg cells to CCR9+ IL-17-producing Treg cells, and blocking IL-6 signalling inhibited this conversion in vitro and ameliorated experimental NEC in vivo.InterpretationCollectively, these data suggested that CCR9+ IL-17-producing Treg cells may be a biomarker of severity and highlight the possibility that antibodies targeting IL-6R could ameliorate NEC by modulating lymphocyte balance. FUND: This work was supported by the Science and Technology Planning Project of Guangdong Province, China (2017A020215100), the Science and Technology Foundation of Guangzhou, China (201704020086 and 201604020154), the Medical Scientific Research Foundation of Guangdong Province, China (A2017304 and A2014704), and the Social Science and Technology Development Foundation of Dongguan, China (2016108101037).

Dataset Information

Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells.

Publications

Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells.

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