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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.

项目总结