IDO-mediated immune regulation in established tumors

IDO 介导的肿瘤免疫调节

• 批准号: 8606194
• 负责人: David H. Munn
• 金额: $ 24.01万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-14 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606194
• 关键词: Address; Adoptive Transfer; Antigens; Automobile Driving; Bioavailable; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; CXCR3 gene; Cancer Therapy Evaluation Program; Cancer Vaccines; Cells; Data; Down-Regulation; Drug usage; Effector Cell; Endothelial Cells; Enzymes; Epitopes; Equilibrium; Event; Goals; Helper-Inducer T-Lymphocyte; Homing; Immune; Immune response; Immune system; Immunologics; Immunosuppression; Inflammation; Inflammatory; Interleukin-2; Mediating; Modeling; Molecular; Mouse Strains; Pathway interactions; Pharmaceutical Preparations; Phase I Clinical Trials; Play; Positioning Attribute; Proliferating; Regulation; Regulatory T-Lymphocyte; Role; Site; T cell response; T-Lymphocyte; Testing; Therapeutic; Time; Transgenic Organisms; Tryptophan 2,3 Dioxygenase; Tumor Antigens; Up-Regulation; Vaccination; Vaccines; Vascular Cell Adhesion Molecule-1; base; cancer immunotherapy; cancer therapy; cell killing; chemokine receptor; exhaustion; immune activation; in vivo; in vivo Model; inhibitor/antagonist; methyl tryptophan; mouse model; neoplastic cell; peripheral tolerance; programs; public health relevance; response; therapeutic vaccine; treatment strategy; tumor; tumor microenvironment

DESCRIPTION (provided by applicant): Hosts with established tumors fail to respond to tumor-associated antigens, and often appear to actively suppress responses to anti-tumor vaccines. This tumor-induced suppression constitutes a fundamental barrier to cancer immunotherapy. During the previous period of support, the project has identified the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) as occupying a pivotal role in coordinating this tumor-induced state of suppression and unresponsiveness. In mouse models, IDO expression directly suppresses CD8+ CTL responses, and potently enhances the suppressive activity of Foxp3+ Tregs. If IDO is inhibited using the IDO-inhibitor drug 1-methyl-tryptophan (1MT), hosts with established tumors become markedly more responsive to anti-tumor vaccines and T cell adoptive transfer. Further, when IDO is blocked, vaccine-induced inflammation becomes able to abrogate Treg-mediated suppression and re-program pre-existing Foxp3+ Tregs into pro-inflammatory T-helper/TH17 cells, resulting in significantly enhanced anti- tumor responses. The proposal will use models of defined TCR-transgenic T cells, therapeutic vaccination of large established tumors, and genetically-defined mouse strains, to test the following hypotheses: Aim 1 - Test the hypothesis that IDO-activated Tregs in established tumors and in vaccine-draining LNs mediate dominant suppression of vaccine-induced CTL and T-helper responses; but when IDO is blocked, vaccine-induced inflammation drives down-regulation of Treg-mediated suppression, re-programming of Tregs into polyfunctional T-helper cells, and IL-2-mediated enhancement of intratumoral CTL effector function. Aim 2 - Test the hypothesis that when IDO is blocked, CTLs become able to undergo full effector maturation in the tumor, mediate tumor-cell killing, and drive epitope-spreading to new CTLs against endogenous tumor antigens; but that activated CTL are still subject to PD-1-mediated mechanisms of clonal exhaustion within the tumor, and synergistically benefit from blockade of the PD-1 pathway. Aim 3 - Test the hypothesis that IDO inhibits CTL homing to the tumor by suppressing upregulation of chemokine receptor CXCR3 on activated CTLs, and by suppressing inflammation-induced VCAM-1 expression on tumor endothelial cells; but that inhibition of IDO allows therapeutic vaccination to create local inflammation within the tumor, driving active recruitment of anti-tumor effector cells. The long-term goal of these studies is to develop clinically-applicable combinations of an IDO-inhibitor drug plus therapeutic anti-tumor vaccines; and to use this combination to abrogate tumor-induced immune suppression and allow effective T cell responses against established tumors. The IDO-inhibitor drug 1-methyl- tryptophan (1MT) is currently entering Phase I clinical trials, so this strategy has high translational potential.

描述（由申请人提供）：已形成肿瘤的宿主无法对肿瘤相关抗原产生反应，并且通常似乎会主动抑制对抗肿瘤疫苗的反应。这种肿瘤诱导的抑制构成了癌症免疫治疗的基本障碍。在之前的支持期间，该项目已确定免疫调节酶吲哚胺2,3-双加氧酶（IDO）在协调这种肿瘤诱导的抑制和无反应状态中发挥着关键作用。在小鼠模型中，IDO 表达直接抑制 CD8+ CTL 反应，并有效增强 Foxp3+ Tregs 的抑制活性。如果使用 IDO 抑制剂药物 1-甲基-色氨酸 (1MT) 抑制 IDO，已形成肿瘤的宿主对抗肿瘤疫苗和 T 细胞过继转移的反应会明显增强。此外，当 IDO 被阻断时，疫苗诱导的炎症能够消除 Treg 介导的抑制，并将预先存在的 Foxp3+ Tregs 重新编程为促炎性 T 辅助细胞/TH17 细胞，从而显着增强抗肿瘤反应。该提案将使用确定的 TCR 转基因 T 细胞模型、已建立的大型肿瘤的治疗性疫苗接种以及基因确定的小鼠品系来测试以下假设： 目标 1 - 测试已建立的肿瘤和疫苗中 IDO 激活的 Tregs 的假设-引流 LN 介导对疫苗诱导的 CTL 和 T 辅助细胞反应的显性抑制；但当 IDO 被阻断时，疫苗诱导的炎症会导致 Treg 介导的抑制下调、Treg 重新编程为多功能 T 辅助细胞以及 IL-2 介导的瘤内 CTL 效应功能增强。 目标 2 - 测试以下假设：当 IDO 被阻断时，CTL 能够在肿瘤中经历完全效应子成熟，介导肿瘤细胞杀伤，并驱动表位扩散到针对内源性肿瘤抗原的新 CTL；但激活的 CTL 仍然受到肿瘤内 PD-1 介导的克隆耗竭机制的影响，并从 PD-1 通路的阻断中协同受益。 目标 3 - 检验 IDO 通过抑制活化 CTL 上趋化因子受体 CXCR3 上调以及抑制肿瘤内皮细胞上炎症诱导的 VCAM-1 表达来抑制 CTL 归巢至肿瘤的假设；但 IDO 的抑制使得治疗性疫苗接种能够在肿瘤内产生局部炎症，从而驱动抗肿瘤效应细胞的主动募集。这些研究的长期目标是开发临床适用的 IDO 抑制剂药物与治疗性抗肿瘤疫苗的组合；并利用这种组合消除肿瘤诱导的免疫抑制，并允许 T 细胞对已形成的肿瘤进行有效的反应。 IDO抑制剂药物1-甲基色氨酸（1MT）目前正进入I期临床试验，因此该策略具有很高的转化潜力。