Stinging the Glioma Immune Landscape

项目总结 免疫检查点抑制剂等免疫疗法对癌症患者产生了深远的影响 生存和生活质量。然而，临床数据现在显示，免疫检查点抑制剂可能只会 具有高突变负荷、T细胞浸润、PD-L1表达、DNA缺陷的患者的受益亚群 错配修复和微卫星不稳定性。综合分析显示，这些有利的 易感因素在胶质母细胞瘤中并不常见。胶质母细胞瘤是一个典型的 一种“免疫寒冷”的肿瘤。尽管如此，仍有一些孤立的区域存在CD8T细胞 胶质母细胞瘤的微环境，但我们不知道是什么导致了这些免疫热点 反应性。这一提议将确定是什么触发了局部适应性免疫反应。到目前为止，大多数 研究的重点是肿瘤内的免疫反应。基于对炎症性疾病的一系列观察 在肿瘤浸润性脑边缘的反应，我们现在专注于更详细的抗肿瘤评估 这一界面上的免疫反应可能与肿瘤本身的免疫反应不同。这一差异是 可能误导了科学界关于潜在反应和缺失关键的生物标记物 对抗肿瘤免疫监测和根除非常重要的途径和机制。在这种情况下 在中枢神经系统的癌症中，邻近的大脑受到“损害”或应激，从而上调 免疫趋化因子。值得注意的是，我们将这种观测向前推进了几步，并创造了地形 肿瘤-中枢神经系统界面的免疫图谱，以便更全面地了解哪些对照局限于 免疫反应性。我们可能会提出的许多关于铀浓缩的观察结果 肿瘤内的免疫反应性很可能适用于其他器官部位，但我们也怀疑 将会有真正独特的针对中枢神经系统的观测。此外，为了让我们优先考虑可用的 免疫治疗策略，这项提议还将描绘先天和适应性手臂 免疫系统的常见运行机制为免疫抑制。引发T细胞的大量涌入 通过抑制性肿瘤间质的促炎激活向其他“冷”肿瘤渗透 已经创造出一种新的刺激物(干扰素基因刺激物)激动剂。刺痛是一种广泛表达的感受器 细胞应激，尤其是连接先天免疫和获得性免疫的细胞质中DNA的存在 系统既通过触发干扰素释放，也通过顺式激活髓系细胞。与大多数不同 其他先天免疫激动剂，刺痛激活可以重新教育肿瘤支持M2巨噬细胞向 促炎性M1表型和逆转髓系来源抑制子的表型 细胞。我们实验室的临床前数据表明，刺痛激动剂在 已建立的小鼠脑胶质瘤模型。最终，我们计划将刺痛激动剂推进到临床试验中， 使用我们独特的放射纹理MRI评估来监测T细胞的渗透。 小灵通398(06/09修订版)

PROJECT SUMMARY Immune therapies such as immune checkpoint inhibitors have had a profound impact on cancer patient survival and quality of life. However, clinical data is now emerging that immune checkpoint inhibitors may only benefit subsets of patients that have high mutational loads, T cell infiltration, PD-L1 expression, defects in DNA mismatch repair, and microsatellite instability. Comprehensive profiling reveals that these favorable predisposing factors are not common within glioblastoma. Glioblastoma represents a prototypical example of an “immunologically cold” tumor. Nonetheless, there are isolated areas in which CD8 T cells are present in the glioblastoma microenvironment but we do not know understand what induces these immune hotspots of reactivity. This proposal will determine what is triggering focal adaptive immune responses. Until now, most studies have focused on immune responses within the tumor. Based on a series of observation of inflammatory responses at the tumor-infiltrative brain edge, we are now focusing on a more detailed evaluation of anti-tumor immune responses at this interface, which likely differs from those in the tumor mass itself. This discrepancy is probably misinforming the scientific community regarding biomarkers of potential response and missing key pathways and mechanisms that are important for antitumor immune surveillance and eradication. In the case of cancer in the CNS, the adjacent brain is “damaged” or stressed, thereby upregulating the expression of immune chemokines. Notably, we are taking this observation several steps further and creating topographical immune atlases of the tumor-CNS interface, in order to more fully understand what controls localized immunological reactivity. Many of the observations that we will potentially make regarding enrichment of immune reactivity within the tumor landscape are likely to hold true for other organ sites, but we also suspect that there will be truly unique CNS-specific observations. Furthermore, in order for us to prioritize available immune therapeutic strategies, this proposal will also be profiling both the innate and adaptive arm of the immune system for common operational mechanisms of immune suppression. To trigger a flood of T cell infiltration into otherwise “cold” tumors through pro-inflammatory activation of suppressive tumor stroma, we have created a novel STING (stimulator of interferon genes) agonist. STING is a widely expressed sensor of cellular stress, specifically the presence of DNA in the cytoplasm that bridges the innate and adaptive immune systems both by triggering interferon release and through cis-activation of myeloid cells. Distinct from most other innate immune agonists, STING activation can re-educate tumor supportive M2 macrophages toward a pro-inflammatory M1 phenotype and can reverse the suppressive phenotype of myeloid-derived suppressor cells. Preclinical data from our laboratory demonstrates that STING agonists have therapeutic activity in established murine models of glioma. Ultimately, we plan to advance STING agonists into clinical trials that can be monitored for T cell infiltration using our unique radiomic textural MRI assessments. PHS 398 (Rev. 06/09)