B7H1 Mediated Immunosuppression in Glioma

B7H1 介导的神经胶质瘤免疫抑制

基本信息

批准号：
8504855
负责人：
ANDREW T PARSA
金额：
$ 32.06万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-17 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8504855
关键词：
1-Phosphatidylinositol 3-Kinase Adoptive Transfer Animal Model Animals Antibodies Antigens Apoptosis Autologous Biological Blocking Antibodies Brain Neoplasms C57BL/6 Mouse CD4 Positive T Lymphocytes CD8B1 gene Cell Surface Proteins Cell surface Cells Cessation of life Coculture Techniques Complement Glioblastoma Glioma Goals Health Helper-Inducer T-Lymphocyte Homologous Gene Immune Immune response Immunodeficient Mouse Immunosuppression Immunosuppressive Agents Immunotherapy Implant Infiltration Ligands Link Malignant Neoplasms Measures Mediating Microglia Modeling Natural Killer Cells PTEN gene Pathway interactions Patient Care Patients Peptides Peripheral Blood Lymphocyte Pharmaceutical Preparations Phenotype Placebos Primary Brain Neoplasms Proteins Reagent Regulatory T-Lymphocyte Specificity Specimen T-Lymphocyte Testing Time Toxic effect Tumor Immunity Tumor-Infiltrating Lymphocytes Vaccinated Vaccination Vaccine Therapy Xenograft procedure cohort effective therapy expression vector glioma cell line implantation in vivo killings kinase inhibitor macrophage monocyte peripheral blood programs receptor response small hairpin RNA tumor tumor growth tumor microenvironment tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma (GBM) is a notoriously immunosuppressive primary brain tumor. The long-term goal of this proposal is to understand the mechanisms of GBM-mediated immunosuppression, identify effective means for reversing immunosuppression, and optimize anti-glioma vaccine therapies. B7-Homologue 1 (B7H1), also known as programmed death ligand 1 (PD-L1), is a cell surface protein that inhibits anti-tumor immunity. It is unique as an immunosuppressive protein because its expression is linked to a fundamental step in oncogenesis: PTEN loss and activation of PI 3-kinase (PI(3)K). This provides potential opportunities for reversal of B7-H1 induction through pharmacological inhibition of the PI(3)K pathway. Another unique feature of B7-H1 is its ability to directly faciliate immunosuppression through multiple mechanisms such as apoptosis of CD8+ T-cells, CD4+ helper T-cells (Thelp) and NK cells, or expansion of immunosuppressive CD4+ regulatory T-cells (Tregs). Expression of B7H1 on circulating monocytes, infiltrating macrophages and resident microglia provides an additional layer of immunoresistance in the tumor microenvironment. Thus, the cell surface expression of B7H1 provides another opportunity to reverse immunosuppression through administration of blocking antibodies against B7H1 or its receptor PD-1. To date, the effects of B7H1 on brain tumor immunity have only been tested using highly passaged glioma cell lines and non-autologous T-cells. Mechanisms of B7H1-mediated immunosuppression have not been fully elucidated. Furthermore, the effects of B7H1 on efficacy of glioma vaccine therapy have not been studied. This proposal seeks to thoroughly characterize the immunosuppressive mechanisms of B7H1 using autologous reagents from GBM patients and animal models of glioma that can be immunologically manipulated. We hypothesize that B7H1 expression in the GBM microenvironment confers immunoresistance that can be effectively reversed by B7H1/PD-1 blockade or pharmacologic inhibition of the PI(3)K pathway. The availability of drugs that inhibit the PI(3)K pathway or block B7-H1 and its receptor PD-1 provides a natural extension of these studies into the realm of patient care.

描述（由申请人提供）：胶质母细胞瘤（GBM）是臭名昭著的免疫抑制原发性脑肿瘤。该提案的长期目标是了解GBM介导的免疫抑制的机制，确定逆转免疫抑制的有效手段，并优化抗脱脂瘤疫苗疗法。 B7---词素1（B7H1），也称为编程死亡配体1（PD-L1），是一种抑制抗肿瘤免疫力的细胞表面蛋白。它是一种免疫抑制蛋白独特的，因为它的表达与肿瘤发生的基本步骤有关：PTEN丢失和PI 3-激酶（PI（PI（3）K）的激活。这为通过药理学抑制PI（3）K途径提供了逆转B7-H1诱导的潜在机会。 B7-H1的另一个独特特征是它可以通过多种机制直接促进免疫抑制，例如CD8+ T细胞的凋亡，CD4+助手T细胞（THELP）和NK细胞，或扩展免疫抑制CD4+调节性T细胞（Tregs）。 B7H1在循环单核细胞，浸润巨噬细胞和常驻小胶质细胞上的表达提供了肿瘤微环境中的额外的免疫力层。因此，B7H1的细胞表面表达提供了另一个机会，通过施用针对B7H1或其受体PD-1的抗体来逆转免疫抑制。迄今为止，B7H1对脑肿瘤免疫的影响仅使用高度传递的神经胶质瘤细胞系和非自动T细胞进行了测试。 B7H1介导的免疫抑制的机制尚未完全阐明。此外，尚未研究B7H1对神经胶质瘤疫苗疗法功效的影响。该提案旨在使用GBM患者的自体试剂和可通过免疫学操纵的神经胶质瘤动物模型的自体试剂彻底表征B7H1的免疫抑制作用机制。我们假设B7H1在GBM微环境中的表达赋予了免疫力，可以通过B7H1/PD-1阻断有效地逆转PI（3）K途径的药理抑制。抑制PI（3）K途径或BLOBL B7-H1及其受体PD-1的药物的可用性可自然地扩展到患者护理领域。