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一种很有前途的治疗癌症的方法，但使用这种疗法的热情由于患者无法获得持续成功的治疗而受到影响。损害抗肿瘤免疫反应最佳激活的主要机制是肿瘤促进免疫抑制网络。T调节性细胞（Tregs）通过直接抑制T细胞、NK细胞和树突状细胞诱导免疫细胞耐受。从临床和临床前研究中获得的令人信服的证据表明，Tregs在肿瘤宿主中增加，这些细胞在癌症患者中的积累是抗肿瘤免疫反应最佳激活的主要障碍之一。Tregs抑制功能的缺失或抑制可增强动物的抗肿瘤免疫应答，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Tregs而不影响CD4和CD8 T效应细胞的功能。我们发现，用抗IL-9抗体中和/阻断IL-9可以抑制Tregs的抑制功能，而不影响CD4和CD8 T效应细胞的功能。此外，肿瘤疫苗联合抗il -9可诱导BALB-neuT和MUC-1耐受转基因小鼠的肿瘤排斥反应。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，并且阻断IL-9可以作为干扰Treg功能以增强肿瘤疫苗抗肿瘤作用的新策略。本提案的目标是：目标1将评估IL-9如何影响Tregs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反应；和Aim 3将评估中和/阻断IL-9对人Tregs的影响。这些研究的信息将揭示控制和操纵Tregs的新策略，以增强肿瘤疫苗接种后的抗肿瘤免疫反应。

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. .