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脑癌；尽管提高了治疗标准(手术、化疗和放射治疗)，但只有不到5%的患者在确诊后存活超过5年。因此，需要对基底膜进行新的治疗。我们和其他人已经证明免疫抑制细胞渗透到基底膜微环境，即调节性T细胞和髓系来源的抑制细胞(MDSC)。MDSCs的特征是髓系细胞分化抗原GR1和CD11b共表达。MDSCs的扩张可以由肿瘤细胞本身产生的刺激骨髓生成和抑制成熟髓系细胞分化的因子触发。我们的初步数据表明，在体外和体内的GBM细胞表达晚期糖基化终产物受体(RAGE)的配体，即S100钙结合蛋白A8(S100A8)和S100A9，已被证明在多种肿瘤模型中介导MDSCs的扩张起关键作用。我们希望验证的假设是，GBM衍生因子在激活MDCs上的信号通路方面发挥主要作用，从而导致免疫抑制和胶质瘤进展。通过促进MDSCs的扩增和激活，GBM衍生的配体在脑癌进展中发挥关键作用，并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免疫治疗新方法的范式转变。这项建议的首要目标是阐明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将验证这样的假设，即GBM衍生的配体通过RAGE信号通路诱导MDSCs的扩张和迁移到肿瘤微环境中。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，我们将验证这样的假设，即在体内阻断RAGE信号通路将阻止脑瘤的进展，并增强T细胞介导的抗GBM免疫。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，导致抑制肿瘤进展，并能够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.