B7H1 Mediated Immunosuppression in Glioma

描述(由申请人提供)：胶质母细胞瘤(GBM)是一种臭名昭著的免疫抑制原发脑瘤。这项建议的长期目标是了解GBM介导的免疫抑制的机制，找出逆转免疫抑制的有效方法，并优化抗胶质瘤疫苗治疗。B7同源蛋白1(B7H1)，又称程序性死亡配体1(PD-L1)，是一种抑制抗肿瘤免疫的细胞表面蛋白。它作为一种免疫抑制蛋白是独一无二的，因为它的表达与肿瘤发生的一个基本步骤有关：PTEN缺失和PI 3-激酶(PI(3)K)的激活。这为通过药物抑制PI(3)K途径逆转B7-H1诱导提供了潜在的机会。B7-H1的另一个独特功能是它能够通过多种机制直接促进免疫抑制，如CD8+T细胞、CD4+辅助T细胞(THelp)和NK细胞的凋亡，或免疫抑制的CD4+调节性T细胞(Tregs)的扩增。B7H1在循环单核细胞、浸润性巨噬细胞和驻留的小胶质细胞上的表达为肿瘤微环境提供了一层额外的免疫抵抗。因此，B7H1的细胞表面表达提供了另一个机会，通过给予针对B7H1或其受体PD-1的封闭抗体来逆转免疫抑制。到目前为止，B7H1对脑肿瘤免疫的影响只在高传代的胶质瘤细胞系和非自体T细胞上进行了测试。B7H1介导的免疫抑制机制尚未完全阐明。此外，B7H1对胶质瘤疫苗治疗效果的影响还没有研究。这项建议试图使用来自GBM患者的自体试剂和可以通过免疫操作的胶质瘤动物模型来彻底表征B7H1的免疫抑制机制。我们假设B7H1在GBM微环境中的表达具有免疫耐药性，B7H1/PD-1的阻断或对PI(3)K通路的药物抑制可以有效地逆转这种耐药。抑制PI(3)K途径或阻断B7-H1及其受体PD-1的药物的可获得性使这些研究自然扩展到患者护理领域。

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.