Role of IL-9 in Treg Biology and Tumor Immunity

IL-9 在 Treg 生物学和肿瘤免疫中的作用

• 批准号: 8624539
• 负责人: SANDRA J GENDLER
• 金额: $ 33.01万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8624539
• 关键词: Address; Adenoviruses; Affect; Animals; Antigens; Antitumor Response; Biology; CA-15-3 Antigen; CD8B1 gene; Cancer Patient; Cancer Vaccines; Cell physiology; Cells; Clinical; Dendritic Cells; Effector Cell; Goals; Human; Immune; Immune response; Immune system; Immunization; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Inflammatory; Interleukin-9; Lead; Learning; Modeling; Mus; Natural Killer Cells; Pathway interactions; Patients; Physiologic pulse; Play; Process; Regulatory T-Lymphocyte; Role; T-Lymphocyte; Time; Transgenic Mice; Tumor Immunity; Vaccination; base; cancer immunotherapy; cancer therapy; cytokine; design; in vivo; inhibiting antibody; migration; novel; novel strategies; preclinical study; public health relevance; research study; tumor; tumor growth; vaccination strategy

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. .

描述（由申请人提供）：尽管癌症免疫疗法是一种有前途的癌症治疗方法，但由于未能对患者进行持续成功的治疗，因此使用这种疗法的热情受到了影响。损害抗肿瘤免疫反应最佳激活的一个主要机制是促进肿瘤的免疫抑制网络。 T 调节细胞 (Treg) 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，Treg 在荷瘤宿主中增加，而这些细胞在癌症患者体内的积累是最佳激活抗肿瘤免疫反应的主要障碍之一。消除或抑制Tregs的抑制功能可以增强抗肿瘤免疫反应并延长动物的存活时间。然而，目前还没有有效的策略来消除或抑制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，肿瘤疫苗接种和抗IL-9的组合在BALB-neuT和MUC-1耐受的转基因小鼠中诱导肿瘤排斥。这些结果使我们推测，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 的阻断可以作为干扰 Treg 功能的新策略，从而增强肿瘤疫苗的抗肿瘤效果。该提案的目标是： 目标 1 将评估 IL-9 如何影响 Tregs 的功能；目标 2 将优化 IL-9 的中和/阻断，以在 BALB-neuT 和 MUC-1 耐受转基因小鼠中诱导抗肿瘤免疫反应；目标 3 将评估中和/阻断 IL-9 对人类 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。 。