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

白细胞介素 9 (IL-9) 在小鼠和人类黑色素瘤的抗癌免疫反应中的作用

• 批准号: 281355799
• 负责人: Dr. Wiebke Prüßmann
• 金额: --
• 依托单位: Klinik für Dermatologie, Allergologie und Venerologie (Hautklinik)
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/281355799?language=en
• 关键词: Interleukin; IL; anticancer; immune; responses

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.

白细胞介素9（IL-9）是一种由T细胞产生的细胞因子，最近已被证明可以提供有效和持久的保护，防止小鼠中B16黑色素瘤的生长。在人类中，产生IL-9的T细胞在黑素瘤转移中减少。然而，IL-9抗癌作用的机制仍未被表征，并且从未在人类癌症中研究过IL-9的作用。在健康个体中，显示T细胞产生的人IL-9是瞬时的，先于其他炎性细胞因子的上调，并且IL-9增强TH 1、TH 2、TH 9和TH 17细胞产生的细胞因子，表明这种细胞因子可能作为炎症放大器起作用。本项目旨在利用一种新的生理学相关的小鼠模型研究IL-9在抑制肿瘤生长中的作用和机制。将BRAF（V600 E）黑素瘤细胞注射到输注有对已知人黑素瘤抗原gp 100和TRP的小鼠同源物特异性的转基因T细胞的野生型小鼠中。为了研究IL-9在人类黑色素瘤反应中的作用，申请人将测量一组罕见且有价值的中等风险的原发性黑色素瘤肿瘤中的IL-9水平，这些肿瘤在厚度上与62名患者相匹配，其中31名患者死亡，31名患者存活，并确定IL-9是否与更好的抗肿瘤反应和提高生存率有关。最后，申请人将研究晚期乳腺癌患者免疫调节治疗前后肿瘤和血液中T细胞产生IL-9的情况。（转移性）黑色素瘤，确定在免疫逃避逆转后IL-9产生是否增加，以及IL-9产生是否预测对免疫疗法的更好响应性。该项目将是小鼠和人类研究的高度协同组合，以评估IL-9作为炎症的引发剂和维持剂以及作为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，并有可能导致基于IL-9的癌症新疗法。