TH9 cells inhibit solid tumor growth and mediate tumor resistance via IL-9 and mast cells.
Major finding: TH9 cells inhibit solid tumor growth and mediate tumor resistance via IL-9 and mast cells.
Approach: Analysis of mice deficient in TH17 cell signaling identified an antitumor function for IL-9.
Impact: Adoptive transfer of TH9 cells or administration of IL-9 may suppress melanoma growth.
Adoptive transfer of T cells has been used effectively to treat melanoma patients, but the role of specific subsets of effector T cells in tumor immunity is not well understood. Purwar and colleagues demonstrate that T-helper type 9 (TH9) cells and production of interleukin (IL)-9, a T-cell cytokine, mediate solid tumor immunity. Mice deficient for another subset of T-helper cells, TH17, exhibited reduced growth of subcutaneous melanoma tumors and increased T-cell tumor infiltration compared with wild-type control animals. Transcriptional profiling of these infiltrating T cells identified Il9 as one of the most highly upregulated genes. Treatment with IL-9–neutralizing antibodies or the absence of IL-9 receptor expression accelerated tumor growth, indicating that tumor inhibition requires IL-9 signaling. Conversely, treatment with recombinant IL-9 (rIL-9) suppressed both melanoma and lung carcinoma growth in wild-type mice and prolonged survival, suggesting that administration of rIL-9 has a protective effect against tumor progression. Among the different effector T-cell subsets, adoptive transfer of TH9 cells showed the strongest reduction in melanoma tumor growth and induced melanoma cell apoptosis in vitro, and this inhibitory effect was mediated in part through IL-9 signaling. In addition, rIL-9–stimulated tumor resistance was dependent on the presence of mast cells, but not B or T cells. Interestingly, IL-9–secreting TH9 cells were detected in normal human peripheral blood and skin but were present in fewer numbers in tumor-infiltrating lymphocytes from patients with metastatic melanoma. These results support a role for IL-9 and TH9 cells in tumor immunity and suggest a strategy for the treatment of melanoma.