Proj 4: Triggers for the Induction of T Cell Dysfunction on T cells in Glioblastoma

项目 4：在胶质母细胞瘤中诱导 T 细胞功能障碍的触发因素

• 批准号: 10684037
• 负责人: VIJAY K. KUCHROO
• 金额: $ 43.68万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-03 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684037
• 关键词: Automobile Driving; Brain; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CTLA4 gene; Cell physiology; Cells; Cerebral Edema; Clinical Management; Clinical Trials; Collaborations; Complement; Cytokine Signaling; Data; Dexamethasone; Dose; Excision; Failure; Functional disorder; Gene Expression; Genes; Glioblastoma; Glucocorticoids; Human; Immune; Immune response; Immune system; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Individual; Inflammation; Investigation; KLRB1 gene; Knowledge; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of lung; Mediating; Mediator; Modeling; Mus; Operative Surgical Procedures; Pathway interactions; Patients; Play; Population; Pre-Clinical Model; RNA; Regulatory T-Lymphocyte; Renal carcinoma; Reporter; Resistance; Role; Signal Transduction; Site; Statistical Data Interpretation; T-Lymphocyte; Testing; Therapeutic; Time; Treatment outcome; Tumor-Infiltrating Lymphocytes; Vaccines; anti-CTLA4; anti-PD-1; anti-tumor immune response; biocomputing; cancer immunotherapy; checkpoint receptors; cytokine; effector T cell; exhaustion; fighting; hormonal signals; immune cell infiltrate; immune checkpoint; immune checkpoint blockade; immunoregulation; improved; melanoma; mouse model; novel; prevent; programmed cell death protein 1; programs; receptor; receptor expression; receptor function; response; single-cell RNA sequencing; steroid hormone; success; synergism; tumor; tumor growth; tumor microenvironment

PROJECT SUMMARY Therapies that block co-inhibitory or checkpoint receptors (eg. CTLA-4, PD-1) have realized the potential of the immune system to successfully fight multiple cancers, including melanoma, lung, and renal cancer. Unfortunately, patients with glioblastoma (GBM) have not benefitted from these checkpoint blockade therapies. This likely reflects the fact that the brain is a site of immune privilege; it has set up a state of inherent immune suppression in order to prevent inflammation that would be detrimental to the host. This immune suppressed state likely underlies the failure of current immunotherapies in GBM. The lack of response to anti-CTLA-4 and anti-PD-1 in GBM raises the issue of whether alternative checkpoints are active in the GBM tumor microenvironment (TME), which need to be identified and exploited to achieve the promise of immunotherapy for GBM. Moreover, GBM patients routinely undergo treatment with high dose glucocorticoid (GC, eg. Decadron), a potent immune suppressive agent, prior to surgical resection and during treatment. This raises the important issue of whether glucocorticoid therapy plays an important role in enhancing the immune suppressed state present in GBM, which in turn further antagonizes the potential of checkpoint blockade therapy. We have identified that the immunoregulatory cytokine IL-27 is a key driver of a “co-inhibitory module” of genes that contains several novel receptors that function as checkpoint receptors. Further, we have identified that both exogenous as well as endogenous GC can promote the expression of multiple checkpoint receptors and that GC cooperates with IL-27 to promote expression of the “co-inhibitory module” and expression of gene programs associated with T cell dysfunction. Based on our preliminary data, we hypothesize that IL-27 and glucocorticoid signaling act in the GBM TME to promote the expression of checkpoint receptors and set the stage for a dominant immune suppression. Indeed, interrogation of the single-cell RNA profiles of the immune infiltrate in human GBM shows significant expression of the IL-27-induced co-inhibitory gene module and signatures indicating active GC signaling. Achieving a thorough understanding of the IL-27 and glucocorticoid signaling circuits within the GBM TME will not only provide a means to understand how GBM tumors set a state of immune suppression but also provide a set of novel targets for improving the immune response to GBM. We propose the following specific aims: 1) Determine the impact of the IL-27 signaling circuit in the GBM tumor microenvironment and 2) Determine how glucocorticoid (GC) signaling contributes to checkpoint receptor expression and induction of a state of immune suppression in GBM.

项目摘要 阻断共抑制或检查点受体的疗法（例如，CTLA-4，PD-1）已经实现了 免疫系统，以成功地打击多种癌症，包括黑色素瘤，肺癌和肾癌。 不幸的是，胶质母细胞瘤（GBM）患者并没有从这些检查点阻断疗法中获益。 这可能反映了这样一个事实，即大脑是一个免疫特权的场所;它已经建立了一种固有的免疫状态， 抑制以防止对宿主有害的炎症。这种免疫抑制 这种状态可能是目前GBM免疫疗法失败的原因。缺乏对抗CTLA-4和 GBM中的抗PD-1引起了GBM肿瘤中是否存在替代检查点的问题 微环境（TME），需要识别和利用，以实现免疫治疗的承诺 对于GBM。此外，GBM患者常规地接受高剂量糖皮质激素（GC，例如，Decadron）， 一种有效的免疫抑制剂，在手术切除之前和治疗期间。这就提出了重要的 糖皮质激素治疗是否在增强免疫抑制状态中起重要作用的问题 存在于GBM中，这反过来又进一步拮抗检查点阻断疗法的潜力。 我们已经确定，免疫调节细胞因子IL-27是基因“共抑制模块”的关键驱动因素， 它含有几种新型的受体，作为检查点受体。此外，我们还发现， 外源性和内源性GC可以促进多种检查点受体的表达， GC与IL-27协同促进“共抑制模块”的表达和基因程序的表达 与T细胞功能障碍有关。基于我们的初步数据，我们假设IL-27和糖皮质激素 信号传导在GBM TME中起作用，以促进检查点受体的表达，并为显性免疫调节奠定基础。 免疫抑制事实上，对人类GBM中免疫浸润的单细胞RNA谱的询问 显示IL-27诱导的共抑制基因模块的显著表达和指示活性GC的特征 信号深入了解GBM中的IL-27和糖皮质激素信号通路 TME不仅提供了一种了解GBM肿瘤如何设定免疫抑制状态的方法， 提供了一组用于改善对GBM的免疫应答的新靶点。我们提出以下具体建议： 目的：1）确定IL-27信号通路在GBM肿瘤微环境中的影响，2）确定 糖皮质激素（GC）信号传导如何促进检查点受体表达和诱导一种状态， GBM中的免疫抑制。