Stinging the Glioma Immune Landscape

项目摘要 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，临床数据显示，免疫检查点抑制剂可能只 具有高突变负荷、T细胞浸润、PD-L1表达、DNA缺陷的患者亚群 错配修复和微卫星不稳定性。综合分析显示，这些有利的 诱发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“免疫冷”肿瘤尽管如此，在淋巴细胞中存在CD 8 T细胞存在的孤立区域。 胶质母细胞瘤微环境，但我们不知道是什么诱导了这些免疫热点， 反应性这项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 研究集中在肿瘤内的免疫反应上。基于对炎症的一系列观察， 在肿瘤浸润性脑边缘的反应，我们现在专注于更详细的评估抗肿瘤 在这个界面上的免疫反应，这可能不同于那些在肿瘤块本身。这种差异是 可能误导了科学界关于潜在反应的生物标志物， 途径和机制是重要的抗肿瘤免疫监视和根除。的情况下 在中枢神经系统中的癌症中，邻近的大脑被“损坏”或受到压力，从而上调 免疫趋化因子值得注意的是，我们正在进一步观察这一现象， 肿瘤-CNS界面的免疫图谱，以便更全面地了解是什么控制了局部 免疫反应性我们可能会就浓缩铀问题提出的许多意见， 肿瘤内的免疫反应性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CNS的观测。此外，为了让我们优先考虑可用的 免疫治疗策略，这项建议也将分析先天和适应性手臂的免疫治疗策略。 免疫系统的共同运作机制是免疫抑制。引发大量T细胞 通过抑制性肿瘤间质的促炎性激活， 创造了一种新的STING（干扰素基因刺激剂）激动剂。STING是一种广泛表达的 细胞应激，特别是细胞质中连接先天性和适应性免疫的DNA的存在 通过触发干扰素释放和通过骨髓细胞的顺式激活来激活系统。区别于大多数 其他先天免疫激动剂，STING激活可以重新教育肿瘤支持M2巨噬细胞， 促炎性M1表型，并可逆转髓源性抑制因子的抑制表型 细胞来自我们实验室的临床前数据表明，STING激动剂在以下方面具有治疗活性： 建立了胶质瘤小鼠模型。最终，我们计划将STING激动剂推进临床试验， 使用我们独特的放射组学纹理MRI评估来监测T细胞浸润。 PHS 398（Rev. 06/09）

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)