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

基本信息

批准号：
10477988
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
项目类别：
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/10477988
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 of activation protein 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 Tumor-infiltrating immune cells Vaccines anti-CTLA4 anti-PD-1 anti-tumor immune response base cancer immunotherapy checkpoint receptors cytokine effector T cell exhaustion fighting hormonal signals 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

项目摘要

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.

项目概要阻断共抑制或检查点受体（例如 CTLA-4、PD-1）的疗法已经实现了免疫系统成功对抗多种癌症，包括黑色素瘤、肺癌和肾癌。不幸的是，胶质母细胞瘤（GBM）患者并未从这些检查点阻断疗法中受益。这可能反映了这样一个事实：大脑是免疫特权的场所，它已经建立了一种固有的免疫状态。抑制以防止对宿主造成困扰的炎症。这种状态可能是目前 GBM 免疫疗法失败的原因：对抗 CTLA-4 和抗 CTLA-4 缺乏反应。 GBM 中的抗 PD-1 引发了替代检查点在 GBM 肿瘤中是否活跃的问题微环境（TME），需要识别和利用以实现免疫治疗的承诺此外，GBM 患者通常接受高剂量糖皮质激素（GC，例如 Decadron）治疗，一种有效的免疫抑制剂，在手术切除之前和治疗期间使用。糖皮质激素治疗是否在增强免疫抑制状态中发挥重要作用的问题存在于 GBM 中，这反过来又进一步对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”的关键驱动因素它包含几种充当检查点受体的新受体。此外，我们还发现这两种受体。外源性和内源性GC可以促进多种检查点受体的表达，并且 GC与IL-27配合促进“共抑制模块”表达及基因程序表达根据我们的初步数据，我们寻找 IL-27 和糖皮质激素。 GBM TME 中的信号传导作用促进检查点受体的表达，并为占主导地位的事实上，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着表达以及表明活跃 GC 的特征全面了解 GBM 内的 IL-27 和糖皮质激素信号通路。 TME 不仅提供了一种了解 GBM 肿瘤如何设置免疫抑制状态的方法，而且还提供了一种方法来了解 GBM 肿瘤如何设置免疫抑制状态为改善 GBM 的免疫反应提供了一组新的目标，我们提出以下具体建议。目标：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) 信号如何促进检查点受体表达和诱导状态 GBM 中的免疫抑制。