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

Nature Medicine volume 18, pages 1248–1253 (2012)Cite this article

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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 (TH17) 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 TH9 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 TH9 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.

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Figure 1: Deficiency of ROR-γ is associated with inhibited melanoma growth and high amounts of tumor lymphocytic infiltration.
Figure 2: High IL-9 expression in ROR-γ− T cells.
Figure 3: The role of IL-9 in melanoma immunity in Il23r−/− mice.
Figure 4: TH9 cells inhibit melanoma growth.
Figure 5: Abrogation of IL-9–IL-9R signaling promotes, and treatment with rIL-9 inhibits melanoma development.
Figure 6: The presence of TH9 cells in human skin and peripheral blood.

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Acknowledgements

This research was supported by grants from US National Institutes of Health to T.S.K. (R01 AI-041707, R01 AI-097128 and P50 CA-093683), R.A.C. (R01-AR-056720 and R03-MH-095529) and A.M.J. (Z01-ES-101586). R.P. received a Research Grant Award from The Skin Cancer Foundation. The authors thank K. Gerrish (US National Institutes of Health) with his help with the microarray analysis. J.-C. Renauld39 (Ludwig Institute, Belgium) provided Il9r−/− mice and the corresponding control mice (Il9r+/−). Neutralizing antibodies to IL-9 (MM9C1) were a kind gift from J.v. Snick (Ludwig Institute, Belgium). Salary support for C.S. was provided by the Swiss National Science Foundation and the Foundation Rene Touraine and for R.A.C. from a Damon Runyon Clinical Investigator Award.

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Authors and Affiliations

  1. Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Rahul Purwar, Christoph Schlapbach, Xiaodong Jiang, Robert C Fuhlbrigge, Rachael A Clark & Thomas S Kupper

  2. Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Sheng Xiao, Wassim Elyaman, Samia J Khoury & Vijay K Kuchroo

  3. Cell Biology Section, National Institute of Environmental Health Science, National Institutes of Health, Research Triangle Park, North Carolina, USA

    Hong Soon Kang & Anton M Jetten

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Contributions

R.P. designed the study, performed and analyzed the experiments, and wrote the manuscript. S.X. and H.S.K. performed experiments. W.E., A.M.J., S.J.K. and V.K.K. discussed the data, provided reagents and edited the manuscript. X.J. provided reagents. C.S., R.A.C. and R.C.F. performed the human T cell experiments, discussed the data and edited the manuscript. T.S.K. designed the study, analyzed the experiments and wrote the manuscript.

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Correspondence to Thomas S Kupper.

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Purwar, R., Schlapbach, C., Xiao, S. et al. Robust tumor immunity to melanoma mediated by interleukin-9–producing T cells. Nat Med 18, 1248–1253 (2012). https://doi.org/10.1038/nm.2856

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