B7H1 Mediated Immunosuppression in Glioma

描述（由申请人提供）：胶质母细胞瘤（GBM）是一种众所周知的免疫抑制性原发性脑肿瘤。该提案的长期目标是了解GBM介导的免疫抑制机制，确定逆转免疫抑制的有效方法，并优化抗胶质瘤疫苗疗法。B7同源物1（B7 H1），也称为程序性死亡配体1（PD-L1），是一种抑制抗肿瘤免疫的细胞表面蛋白。它是一种独特的免疫抑制蛋白，因为它的表达与肿瘤发生中的一个基本步骤有关：PTEN丢失和PI 3-激酶（PI（3）K）的激活。这为通过PI（3）K途径的药理学抑制逆转B7-H1诱导提供了潜在的机会。B7-H1的另一个独特特征是其通过多种机制直接促进免疫抑制的能力，所述机制例如CD 8 + T细胞、CD 4+辅助T细胞（Thelp）和NK细胞的凋亡，或免疫抑制性CD 4+调节性T细胞（THELP）的扩增。B7 H1在循环单核细胞、浸润性巨噬细胞和常驻小胶质细胞上的表达在肿瘤微环境中提供了额外的免疫抗性层。因此，B7 H1的细胞表面表达提供了通过施用针对B7 H1或其受体PD-1的阻断抗体来逆转免疫抑制的另一个机会。迄今为止，B7 H1对脑肿瘤免疫的影响仅使用高度传代的神经胶质瘤细胞系和非自体T细胞进行了测试。B7 H1介导的免疫抑制机制尚未完全阐明。此外，尚未研究B7 H1对神经胶质瘤疫苗治疗功效的影响。该提案旨在使用来自GBM患者的自体试剂和可以免疫操纵的胶质瘤动物模型来彻底表征B7 H1的免疫抑制机制。我们假设B7 H1在GBM微环境中的表达赋予免疫耐受性，该免疫耐受性可通过B7 H1/PD-1阻断或PI（3）K途径的药理学抑制而有效逆转。抑制PI（3）K通路或阻断B7-H1及其受体PD-1的药物的可用性为这些研究提供了一个自然的延伸到患者护理领域。

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.