Improving Glioma Immunotherapy Efficacy by Regulating Tumor Inflammation

项目摘要 诊断为胶质母细胞瘤（GBM）的患者的中位总生存期不到两年， 在接受多模式治疗后。多种因素导致了这种治疗抵抗，包括：1） 2）GBM的分子异质性， 克服靶向治疗的重叠逃避机制; 3）使GBM 对免疫疗法有抵抗力。因此，存在对解决GBM治疗方法的未满足的需求， 多重抗性机制 晚期糖基化终末产物受体（receptor for advanced glycation end products，RECEPTOR）是免疫球蛋白家族的一员， 作为非酶糖化产物的跨膜受体被发现， 蛋白质的氧化。GBM由胶质瘤细胞表达，并被GBM肿瘤中存在的配体激活 微环境（TME）。激活GBM刺激多种信号通路，促进GBM 进展最近，我们证明了基因切除胶质瘤细胞内的凋亡抑制了多种神经胶质细胞的增殖， 致癌通路不仅调节胶质瘤的生长和侵袭，而且提高了化疗的疗效。 免疫疗法通过促进免疫学上“允许的”TME。我们还发现， 增强免疫疗法的疗效。基于这些观察，我们建议评估 抑制作为GBM的多方面疗法。 我们的中心假设是，β-淀粉样蛋白失活不仅会抑制致癌途径， 对GBM生长和侵袭很重要，而且增强对免疫疗法应答。三名独立 提出了目标。目的1探讨肿瘤消融增强机体抗肿瘤免疫的机制 在同基因小鼠GBM模型中的反应。这项目标的发现将揭示新的战略， 增强这些耐药肿瘤的免疫治疗功效。目标2将衡量小的 分子抑制剂与免疫疗法。为此，我们将进行临床前研究，以优化 用于未来GBM临床试验的抗肿瘤抑制剂的给药方案。最后，目标3将确定 免疫疗法对肿瘤消融的抵抗。这一目标将确定的机制， 如S100 A9减弱肿瘤免疫应答。 这些目标中的任何一个目标的成功都得到了令人信服的初步数据的支持，预计将导致 开发新的和急需的GBM疗法。

PROJECT SUMMARY Patients diagnosed with glioblastoma (GBM) have a median overall survival of less than two years even after receiving multimodal therapies. Multiple factors account for this treatment resistance including: 1) Inability of therapies to cross the blood-brain barrier to reach invading cells; 2) GBM’s molecular heterogeneity and overlapping escape mechanisms that overcome targeted therapies; 3) Evasive mechanisms that render GBMs resistant to immunotherapy. Therefore, there is an unmet need for GBM treatment approaches that address multiple resistance mechanisms. The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily which was discovered as a transmembrane receptor for the products of nonenzymatic glycation and oxidation of proteins. RAGE is expressed by glioma cells and is activated by its ligands present in GBM tumor microenvironment (TME). Activation of RAGE stimulates multiple signaling pathways that promote GBM progression. Recently, we demonstrated that genetic ablation of intracellular RAGE in gliomas inhibited multiple oncogenic pathways that not only regulated glioma growth and invasion, but also, improved the efficacy of immunotherapies by promoted an immunologically “permissive” TME. We also discovered that RAGE ablation in TME enhances the efficacy of immunotherapy. Based on these observations, we propose to evaluate RAGE inhibition as a multifaceted therapy for GBM. Our central hypothesis is that RAGE inactivation will not only suppress oncogenic pathways that are important for GBM growth and invasion, but also, enhance responses to immunotherapy. Three independent aims are proposed. Aim 1 will determine the mechanism of RAGE ablation on enhancing the anti-tumor immune responses in syngeneic mouse GBM models. Findings from this Aim will uncover novel strategies that could enhance immunotherapy efficacy in these resistant tumors. Aim 2 will measure the synergistic effects of small molecule RAGE inhibitors with immunotherapy. In this Aim, we will perform the pre-clinical studies to optimize the dosing regimen of RAGE inhibitors for future GBM clinical trials. Finally, Aim 3 will Identify mechanisms of immunotherapy resistance to RAGE ablation. This Aim will identify the mechanisms by which RAGE ligands such as S100A9 attenuate tumor immune responses. Success of any of these aims, which are supported by compelling preliminary data, is expected to lead to the development of novel and critically needed GBM therapies.