PTEN, Tregs and MDSCs in the tumor microenvironment

肿瘤微环境中的 PTEN、Treg 和 MDSC

• 批准号: 10218066
• 负责人: David H. Munn
• 金额: $ 34.77万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218066
• 关键词: Adoptive Cell Transfers; Agonist; Antigens; Antitumor Response; Back; Blood Circulation; Bone Marrow; Cell Death; Cell Lineage; Cells; Dendritic Cells; Drug Combinations; Failure; Feedback; Feeds; Human; Immune; Immune response; Immune system; Immunologics; Immunotherapy; Inflammation; Inflammatory; Interferons; Interleukin-1; Interleukin-1 alpha; Interleukin-12; Knockout Mice; MDM2 gene; Myelogenous; Myeloid Cells; PTEN gene; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phenotype; Population; Ramp; Reactive Oxygen Species; Regulatory T-Lymphocyte; Respiratory Burst; Signal Transduction; T-Lymphocyte; TP53 gene; Testing; Therapeutic; Time; Translations; Tumor Antigens; Vaccines; anti-tumor immune response; cancer therapy; chemotherapy; clinical application; clinical development; cytokine; exhaust; immune checkpoint blockade; immunogenic; inflammatory milieu; inhibitor/antagonist; monocyte; neoplastic cell; novel; programs; response; transcription factor; tumor; tumor microenvironment

Tumors express many immunogenic antigens, but in most cases the spontaneous response to these antigens by host T cells is poor. This represents a major problem for both immunotherapy and immunogenic chemotherapy. We now describe a population of highly immunogenic dendritic cells (DCs), arising in tumors during immunotherapy, which share attributes of “conventional” CD103+ cDCs, but which also express lineage-markers of monocytic MDSCs. The scientific premise of the proposal is that this population of “dual- phenotype” Ly6c+/CD103+ DCs is critical to anti-tumor immune responses during immunotherapy, and that it is possible to therapeutically amplify and increase these cells so as to markedly enhance the effect of immunotherapy. Aim 1 will test the hypothesis that the Ly6c+/CD103+ DCs arise via rapid differentiation of immature myeloid cells (monocytic MDSCs) in the tumor milieu, via a pathway that requires re-activation of classical DC-lineage transcription factors. The signal that initially drives this differentiation step is inflammation from dying tumor cells, but this is then rapidly amplified by inflammatory signals from activated T cells (positive feedback loop). The hypothesis predicts that Ly6c+/CD103+ DCs are critical for anti-tumor immune responses because they are the only cells in the tumor capable of re-activating anergic/exhausted T cells. Aim 2 will test the hypothesis that the key mechanism controlling differentiation of Ly6c+/CD103+ DCs is the transcription factor p53 expressed in MDSCs. The hypothesis predicts that p53 acts by inducing expression of the pro- inflammatory transcription factor IRF5; and that the upstream signal for p53 activation is the cell-intrinsic respiratory burst (reactive oxygen species) produced in response to inflammatory cytokines. Aim 3 will test the translationally-relevant hypothesis that pharmacologic activation of the p53 pathway, using clinically-applicable p53-agonist drugs, will drive the differentiation of increased numbers of Ly6c+/CD103+ DCs during immunotherapy, thus markedly enhancing and prolonging the anti-tumor immune response. To support translation of this approach to humans, this aim will also test the prediction that human myeloid DCs are controlled by an analogous p53-driven, IRF5-dependent maturation pathway. The translational importance of these findings is that they identify myeloid-lineage p53 as a previously unsuspected target for immunotherapy, which can be targeted by existing p53-agonist drugs already under clinical development for other indications.

肿瘤表达许多免疫原性抗原，但在大多数情况下，对这些抗原的赞助反应 由宿主T细胞不良。这代表了免疫疗法和免疫原性的主要问题 化学疗法。现在，我们描述了高度免疫原性树突状细胞（DC）的种群，在肿瘤中产生 在免疫疗法期间，具有“常规” CD103+ CDC的属性，但也表达 单核细胞MDSC的谱系标记。该提议的科学前提是，“双重 - 表型” LY6C+/CD103+ DCS对于免疫疗法期间的抗肿瘤免疫复杂至关重要，并且是 可以热扩增并增加这些细胞，以显着增强 免疫疗法。 AIM 1将检验LY6C+/CD103+ DCS的假设是通过快速分化而产生的 肿瘤环境中未成熟的髓样细胞（单核细胞MDSC），通过需要重新激活的途径 经典DC-LINEGE转录因子。最初驱动这种差异步骤的信号是炎症 从垂死的肿瘤细胞中，但这被激活的T细胞的炎症信号迅速扩大（阳性 反馈循环）。 LY6C+/CD103+ DCS的假设预测对于抗肿瘤免疫复杂至关重要 因为它们是肿瘤中唯一能够重新激活厌食症/耗尽的T细胞的细胞。 AIM 2将测试 控制LY6C+/CD103+ DC的关键机制是转录的假设 在MDSC中表达的因子p53。假设预测p53通过诱导的表达作用 炎症转录因子IRF5;并且p53激活的上游信号是细胞中心 响应炎症细胞因子产生的呼吸爆发（活性氧）。 AIM 3将测试 使用临床上适用的p53途径的药物激活与翻译相关的假设 p53激动剂，将推动在ly6c+/cd103+ dc中增加的分化 免疫疗法，因此显着增强和延长了抗肿瘤免疫反应。支持 这种方法翻译为人类，这一目标还将测试人类髓样DC是的预测 由类似p53驱动的IRF5依赖性成熟途径控制。翻译重要性 其中的结果是，他们将髓样linege p53识别为先前未刺的目标 免疫疗法，可以由已经在临床发育中的现有p53激动剂药物来靶向 其他迹象。