Role of IL-9 in Treg Biology and Tumor Immunity

描述（由申请人提供）：尽管癌症的免疫疗法是治疗癌症的一种有前景的方法，但使用这种疗法的热情受到未能实现患者持续成功治疗的事实的影响。损害抗肿瘤免疫应答的最佳激活的主要机制是肿瘤促进免疫抑制网络。调节性T细胞（TCRs）通过直接抑制T细胞、NK细胞和树突状细胞来诱导免疫细胞耐受。从临床和临床前研究中获得的令人信服的证据表明，在荷瘤宿主中T细胞增加，并且这些细胞在癌症患者中的积累是抗肿瘤免疫应答的最佳激活的主要障碍之一。消除或抑制TGFAP的抑制功能可增强抗肿瘤免疫应答并延长动物的生存期。然而，目前还没有有效的策略来消耗或抑制T细胞而不影响CD 4和CD 8 T效应细胞的功能。我们鉴定了用抗IL-9抗体中和/阻断IL-9抑制了Tcl 3的抑制功能，而不影响CD 4和CD 8 T效应细胞的功能。此外，肿瘤疫苗接种和抗IL-9的组合在BALB-neuT和MUC-1耐受转基因小鼠中诱导肿瘤排斥。这些结果使我们假设IL-9在炎症（肿瘤生长）过程中在Treg生物学中发挥作用，增强/促进这些细胞的抑制功能，并且IL-9的阻断可以用作干扰Treg功能以增强肿瘤疫苗的抗肿瘤作用的新策略。本提案的目的是：目的1将评价IL-9如何影响Tcl 3的功能;目的2将优化IL-9的中和/阻断，以诱导BALB-neuT和MUC-1耐受转基因小鼠的抗肿瘤免疫应答;目的3将评价中和/阻断IL-9对人Tcl 3的影响。这些研究的信息将揭示新的策略，用于控制和操纵THBE，以增强肿瘤疫苗接种后的抗肿瘤免疫应答。. 公共卫生相关性：我们的研究结果首次表明，IL-9的中和抑制了TGFAP的抑制功能，并增强了肿瘤疫苗接种后的抗肿瘤反应。该提案的目标之一是了解IL-9在Treg生物学中的作用，并优化抗IL-9的使用以增强抗肿瘤反应。我们坚信，通过靶向IL-9来控制或操纵T细胞功能的概念可以形成开发如何处理这些细胞而不影响效应T细胞的策略的基础。总的来说，本提案中提出的研究将揭示控制和操纵免疫系统的策略，以在耐受宿主中开发更有效的免疫疗法。

DESCRIPTION (provided by applicant): Although immunotherapy of cancer is a promising approach for the treatment of cancer the enthusiasm for using this therapy is tempered by the fact that consistently successful treatment of patients is not achieved. A major mechanism impairing the optimal activation of an antitumor immune response is the promotion of networks of immune suppression by the tumor. T regulatory cells (Tregs) induce immune cell tolerance by directly inhibiting T cells, NK cells and dendritic cells. Compelling evidence obtained from both clinical and pre-clinical studies indicate that Tregs are increased in tumor bearing hosts and the accumulation of these cells in cancer patients is one of the main barriers for the optimal activation of an antitumor immune response. Depletion or inhibition of the suppressive function of Tregs enhances the antitumor immune responses and prolonged the survival of animals. However, currently there are no effective strategies to deplete or inhibit Tregs without affecting function of CD4 and CD8 T effector cells. We identified that neutralization/blockade of IL-9 with anti-IL-9 antibodies inhibits the suppressive function of Tregs without affecting the function of CD4 and CD8 T effector cells. Furthermore, the combination of tumor vaccination and anti-IL-9 induce tumor rejection in BALB-neuT and MUC-1 tolerant transgenic mice. These results led us to hypothesize that IL-9 play a role in Treg biology during the inflammatory (tumor growth) process enhancing/promoting the suppressive function of these cells and that the blockade of IL-9 could serve as a novel strategy to perturb the function of Tregs to enhance the antitumor effect of tumor vaccines. The objectives of this proposal are: Aim 1 will evaluate how IL-9 influences the function of Tregs; Aim 2 will optimize the neutralization/blockade of IL-9 for the induction of antitumor immune responses in BALB-neuT and MUC-1 tolerant transgenic mice; and Aim 3 will evaluate the effect of neutralizing/blocking IL-9 on human Tregs. The information of these studies will reveal new strategies for controlling and manipulating Tregs in order to enhance the antitumor immune response following tumor vaccination. . PUBLIC HEALTH RELEVANCE: For the first time our results show that neutralization of IL-9 inhibits the suppressive function of Tregs and enhances antitumor responses following tumor vaccination. One of the goals of this proposal is to understand the role of IL-9 in Treg biology and optimize the use of anti-IL-9 to enhance antitumor responses. We strongly believe that with the concept of targeting IL-9 to control or manipulate the function of Tregs could form the basis to develop strategies how to deal with these cells without affecting effector T cells. Overall the studies proposed in this proposal will reveal strategies for controlling and manipulating the immune system to develop more effective immunotherapies in tolerant hosts.