Interleukin 9 (IL-9) in anticancer immune responses against melanoma in mice and human

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Interleukin 9 (IL-9) is a cytokine produced by T cells that has recently been shown to provide potent and long-lasting protection against B16 melanoma growth in mice. In humans, IL-9 producing T cells are decreased in melanoma metastases. However, the mechanisms of IL-9 anticancer effects remain uncharacterized and effects of IL-9 have never been studied in a human cancer. In healthy individuals, it was shown that human IL-9 production by T cells was transient, preceded the up-regulation of other inflammatory cytokines and that IL-9 enhanced cytokine production by TH1, TH2, TH9 and TH17 cells, suggesting this cytokine may function is as an amplifier of inflammation.Because of its remarkable ability to stop B16 melanoma growth, this project aims to study the role and mechanism of IL-9 in suppressing tumor growth using a novel physiologically relevant mouse model. BRAF(V600E) melanoma cells will be injected into wild type mice infused with transgenic T cells specific for mouse homologues of the known human melanoma antigens gp100 and TRP. Using melanoma tumor cells similar to those seen in patients will lead to a better understanding of the ability of T cells making IL-9 to attack and destroy these tumors.To study IL-9 in human melanoma responses, the applicant will measure IL-9 levels in a rare and valuable set of primary melanoma tumors of intermediate risk that are matched in thickness from 62 patients, 31 who died and 31 who survived, and determine if IL-9 is associated with better antitumor responses and improved survival. Lastly, the applicant will study IL-9 production by T cells in tumors and blood in patients before and after immunomodulatory therapies for advanced (metastasized) melanoma, determining if IL-9 production is increased after reversal of immune evasion and if IL-9 production predicts a better responsiveness to immunotherapy.In summary, this project will be a highly synergistic combination of mouse and human studies to evaluate a novel role for IL-9 as an initiator and sustainer of inflammation and as a novel therapy for melanoma. If successful, these studies will enhance our basic understanding of IL-9 biology and also have the potential to lead to novel IL-9-based therapies for cancer.