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

白细胞介素9 （IL-9）是一种由T细胞产生的细胞因子，最近被证明对小鼠B16黑色素瘤的生长提供有效和持久的保护。在人类中，产生IL-9的T细胞在黑色素瘤转移中减少。然而，IL-9抗癌作用的机制尚不清楚，IL-9在人类癌症中的作用也从未被研究过。在健康个体中，研究表明，人类T细胞产生IL-9是短暂的，先于其他炎症细胞因子的上调，IL-9可增强TH1、TH2、TH9和TH17细胞产生的细胞因子，表明该细胞因子可能是炎症的放大器。由于IL-9具有显著的抑制B16黑色素瘤生长的能力，本项目旨在通过一种新的生理相关小鼠模型研究IL-9在抑制肿瘤生长中的作用和机制。将BRAF（V600E）黑色素瘤细胞注射到野生型小鼠体内，注入对已知人类黑色素瘤抗原gp100和TRP的小鼠同源物特异性的转基因T细胞。使用与患者相似的黑色素瘤肿瘤细胞将有助于更好地了解T细胞制造IL-9攻击和摧毁这些肿瘤的能力。为了研究IL-9在人类黑色素瘤应答中的作用，申请人将测量一组罕见且有价值的中等风险原发性黑色素瘤肿瘤中的IL-9水平，这些肿瘤来自62例患者，其中31例死亡，31例存活，并确定IL-9是否与更好的抗肿瘤应答和改善的生存率相关。最后，申请人将研究晚期（转移性）黑色素瘤免疫调节治疗前后患者肿瘤和血液中T细胞产生的IL-9，确定IL-9的产生是否在免疫逃避逆转后增加，以及IL-9的产生是否预示着对免疫治疗的更好反应。总之，该项目将是小鼠和人类研究的高度协同结合，以评估IL-9作为炎症的启动者和维持者以及黑色素瘤的新疗法的新作用。如果成功，这些研究将增强我们对IL-9生物学的基本理解，也有可能导致新的基于IL-9的癌症治疗方法。

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.