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

• Published in: Nature medicine Vol. 18; no. 8; pp. 1248 - 1253
• Main Authors: Purwar, Rahul, Schlapbach, Christoph, Xiao, Sheng, Kang, Hong Soon, Elyaman, Wassim, Jiang, Xiaodong, Jetten, Anton M, Khoury, Samia J, Fuhlbrigge, Robert C, Kuchroo, Vijay K, Clark, Rachael A, Kupper, Thomas S
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2012; Nature Publishing Group
• Subjects: 631/250/127/1213; 692/699/67/1813/1634; 692/699/67/580; Allergies; Animals; Biomedical and Life Sciences; Biomedicine; Blood; Cancer Research; Cancer Vaccines; Carcinoma, Lewis Lung - immunology; Carcinoma, Lewis Lung - pathology; Care and treatment; Cellular immunity; Cytokines; Diagnosis; Disease Progression; Gene expression; Gene Expression Profiling; Genetic aspects; Health aspects; Homeodomain Proteins - genetics; Humans; Immune system; Immunotherapy, Adoptive; Infectious Diseases; Interleukin-9; Interleukin-9 - analysis; Interleukin-9 - biosynthesis; Interleukin-9 - genetics; Interleukin-9 - physiology; Lesions; Lymphatic Metastasis; Lymphocytes; Lymphocytes, Tumor-Infiltrating - immunology; Mast Cells - drug effects; Mast Cells - immunology; Melanoma; Melanoma - chemistry; Melanoma - immunology; Melanoma - pathology; Melanoma - secondary; Melanoma, Experimental - immunology; Melanoma, Experimental - pathology; Melanoma, Experimental - therapy; Metabolic Diseases; Metastasis; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Medicine; Neoplasm Proteins - analysis; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; Neurosciences; Nuclear Receptor Subfamily 1, Group F, Member 3 - deficiency; Nuclear Receptor Subfamily 1, Group F, Member 3 - genetics; Radiation Chimera; Receptors, Interleukin - deficiency; Receptors, Interleukin - genetics; Recombinant Fusion Proteins - physiology; Skin - immunology; Skin cancer; Skin Neoplasms - chemistry; Skin Neoplasms - immunology; Skin Neoplasms - pathology; T cells; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Tumor Burden; Tumors; Vaccination; United States
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.2856

In this issue, Thomas Kupper and colleagues report that mice deficient for ROR-γ or interleukin-23 (IL-23) receptor showed impaired melanoma growth. Tumor growth inhibition was dependent in part on IL-9 and T helper type 9 (T H 9) cells. Moreover, the authors showed that IL-9 acts on mast cells rather than T or B cells to mediate its antitumor effects and that T H 9 cells are present in human blood and skin, suggesting that a role for T H 9 cells in human tumor immunity should be explored. 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.