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: 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
• 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

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.

项目总结 阻断共抑制或检查点受体的治疗(例如。CTLA-4、PD-1)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，即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，以防止对宿主有害的炎症。这种免疫力受到抑制 国家可能是目前GBM免疫疗法失败的根本原因。对抗CTLA-4和 GBM中的抗PD-1抗体提出了在GBM肿瘤中是否存在替代检查点的问题 需要识别和利用的微环境(TME)，以实现免疫治疗的前景 对于GBM。此外，GBM患者常规接受大剂量糖皮质激素(GC)治疗。Decadron)， 一种有效的免疫抑制剂，在手术切除前和治疗期间。这就提出了重要的 糖皮质激素治疗是否在改善免疫抑制状态中起重要作用 存在于基底膜，这反过来又进一步对抗检查点封锁治疗的可能性。 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 它含有几种新的受体，起着检查点受体的作用。此外，我们已经确认，两者 外源性和内源性GC均可促进多种检查点受体的表达 GC协同IL-27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。根据我们的初步数据，我们假设IL-27和糖皮质激素 信号在GBM TME中起作用，促进Checkpoint受体的表达，为显性 免疫抑制。事实上，人类基底膜免疫浸润物的单细胞RNA图谱的询问 显示IL-27诱导的共抑制基因模块的显著表达，并显示活跃的GC信号 发信号。对白介素27和糖皮质激素信号通路有深入的了解 TME不仅将提供一种手段来了解GBM肿瘤如何设置免疫抑制状态，而且还将 为提高对GBM的免疫应答提供了一系列新的靶点。我们提出了以下具体建议 目的：1)确定IL-27信号通路在基底膜肿瘤微环境中的作用；2)确定 糖皮质激素(GC)信号如何参与检查点受体的表达和诱导 基底膜的免疫抑制。