Unraveling and targeting distinct immunosuppressive mechanisms in GBM

胶质母细胞瘤(GBM)是最常见和最具侵袭性的成人脑肿瘤，85%的患者在两年内死亡。迫切需要新的靶向治疗，但尽管努力根据分子和遗传特征对患者进行亚型划分，但现有的亚型仍未能指导靶向治疗策略。免疫检查点抑制剂(ICI)由于在延长患者生命方面的治疗效果而改变了几种癌症的治疗模式，但由于它们的无能和免疫抑制特性，迄今在GBM中失败了。为此，目前还不清楚基底膜肿瘤微环境中的哪些途径和信号导致了这种治疗失败。我们的实验室最近在ICI无反应性IDHwt-GBM中发现了两种免疫抑制亚型，一种是免疫废弃且高度血管生成(TIMElow)，另一种是免疫富集型，具有更高功能的血脑屏障(TIMEHigh)。我认为，不同的机制导致了整体的免疫抑制，需要采用亚型特异性策略来唤起免疫反应。使用基因工程的GBM小鼠肿瘤模型和人GBM组织，我将通过从功能上表征两种时间GBM亚型的血管免疫环境来验证我的假设，并设计特定和新颖的组合免疫肿瘤学精确治疗策略，以增加TIMElow GBM中的T细胞渗透和活性，并抵消TIMEHigh GBM中免疫抑制的免疫细胞功能。即将到来的部分用途改变和批准的药物将有望指导未来的试验，以及时唤起足够的免疫反应，延长GBM患者的寿命。

Glioblastoma (GBM) is the most frequent and aggressive adult brain tumor, with 85% of patients dying within two years. Novel targeted therapies are urgently required, but despite efforts to subtype patients based on molecular and genetic profiles, available subtypes have yet failed to direct targeted treatment strategies. Immune checkpoint inhibitors (ICI) have created a paradigm shift in the treatment of several cancers due to their therapeutic efficacy in extending patient lives, but so far have failed in GBMs, due to their anergic and immunosuppressive characteristics. To this end, it remains unknown which pathways and signals in the GBM tumor microenvironment contribute to such therapy failure. Our laboratory has recently identified two immunosuppressive subtypes in ICI-non-responding IDHwt-GBM that are either immune-deserted and highly angiogenic (TIMElow) or immune-enriched with a more functional blood-brain barrier (TIMEhigh). I propose that different mechanisms cause the overall immunosuppression for which subtype-specific strategies need to be employed to evoke an immune response. Using genetically engineered GBM mouse tumor models and human GBM tissues, I will test my hypothesis by functionally characterizing the vascular immune environment in both TIME GBM subtypes and design specific and novel combinatorial immuno-oncology precision treatment strategies that increase T cell infiltration and activity in TIMElow GBM, and counteract the immunosuppressive immune cell functions in TIMEhigh GBM. Results forthcoming with partly repurposed and approved drugs will hopefully guide future trials in a timely manner to evoke an adequate immune response and prolong lifespan in GBM patients.