Crosstalk between glioma cells & immune cells in the tumor microenvironment: Ther

描述（申请人提供）：多形性胶质母细胞瘤（GBM）是成人最常见的原发性脑癌；尽管提高了治疗标准（手术、化疗和放疗），但不到5%的患者在诊断后存活超过5年。因此，需要新的治疗GBM的方法。我们和其他人已经证明免疫抑制细胞浸润GBM微环境，即调节性T细胞和髓源性抑制细胞（MDSC）。MDSCs的特点是骨髓细胞系分化抗原GR1和CD11b的共表达。MDSCs的扩增可由肿瘤细胞自身产生的因子触发，这些因子刺激骨髓生成，抑制成熟骨髓细胞的分化。我们的初步数据表明，GBM细胞在体外和体内均表达晚期糖基化终产物（RAGE）受体的配体，即S100钙结合蛋白A8 （S100A8）和S100A9，这两种配体在几种癌症模型中介导MDSCs的扩增中发挥了关键作用。我们希望验证的假设是gbm衍生因子在激活MDCS的信号通路中起主要作用，导致免疫抑制和胶质瘤进展。GBM衍生配体在脑癌进展中发挥关键作用，并通过促进MDSCs的扩张和激活来阻碍有效的抗肿瘤免疫反应，这一发现将导致旨在抑制MDSCs扩张和激活的GBM新型免疫治疗方法的发展范式转变。本提案的总体目标是阐明MDSCs在胶质瘤进展中的作用及其对新型免疫疗法发展的影响。因此，SA 1将验证gbm衍生的配体信号通过RAGE途径诱导MDSCs向肿瘤微环境的扩张和迁移的假设。在SA2中，我们将在体外和体内验证胶质瘤诱导的MDSCs抑制抗肿瘤效应T细胞功能的假设。在SA3中，我们将验证在体内阻断RAGE信号通路会阻碍脑肿瘤进展并增强T细胞介导的抗gbm免疫的假设。这些结果将为新的抗gbm免疫治疗策略铺平道路，旨在操纵MDSCs的扩张和激活；导致肿瘤进展的抑制和诱导有效的抗肿瘤免疫应答免疫治疗。

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults; in spite of improved standard of care (surgery, chemotherapy, and radiation), less than 5% of the patients survive more than 5 years post-diagnosis. Thus, new treatments for GBM are needed. We and others have shown that immune suppressive cells infiltrate the GBM microenvironment, i.e., regulatory T cells and myeloid derived suppressor cells (MDSC). MDSCs are characterized by co-expression of the myeloid cell-lineage differentiation antigen GR1 and CD11b. Expansion of MDSCs can be triggered by factors produced by the tumor cells themselves, which stimulate myelopoiesis and inhibit the differentiation of mature myeloid cells. Our preliminary data demonstrates that GBM cells in vitro and in vivo express ligands for the receptor for advanced glycation end products (RAGE), i.e., S100 calcium binding protein A8 (S100A8) and S100A9, which have been shown to play a critical role in mediating the expansion of MDSCs in several cancer models. The hypothesis we wish to test is that GBM-derived factors play a major role in activating signaling pathways on MDCS leading to immune suppression and glioma progression. The discovery that GBM-derived ligands play a critical role in brain cancer progression and hamper effective anti-tumor immune responses by promoting the expansion and activation of MDSCs, will lead to a paradigm shift in the development of novel immune therapeutic approaches for GBM aimed at inhibiting MDSCs expansion and activation. The overarching goal of this proposal is to elucidate the role of MDSCs in glioma progression and their impact on the development of novel immune therapeutics. Thus, SA 1 will test the hypothesis that GBM-derived ligands signaling via the RAGE pathway induce the expansion and migration of MDSCs into the tumor microenvironment. In SA2, we will test the hypothesis that glioma-induced MDSCs inhibit anti-tumor effector T cells' functions in vitro and in vivo. In SA3 we will test the hypothesis that blocking the RAGE signaling pathway in vivo will hinder brain tumor progression and enhance T cell mediated anti-GBM immunity. These results will pave the way for novel anti-GBM immune therapeutic strategies aimed at manipulating the expansion and activation of MDSCs; leading to inhibition of tumor progression and enabling the induction of effective anti-tumor immunity in response to immune therapeutics.