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分型，但可用的亚型尚未指导靶向治疗策略。免疫检查点抑制剂（ICI）由于其延长患者生命的治疗功效而在几种癌症的治疗中创造了范式转变，但由于其无反应性和免疫抑制特性，迄今为止在GBM中失败。为此，GBM肿瘤微环境中的哪些途径和信号导致这种治疗失败仍然是未知的。我们的实验室最近在ICI-无反应IDHwt-GBM中鉴定了两种免疫抑制亚型，它们要么是免疫废弃的和高度血管生成的（TIMElow），要么是免疫富集的，具有更功能的血脑屏障（TIMEhigh）。我建议，不同的机制导致整体免疫抑制亚型特异性的策略，需要采用唤起免疫反应。使用基因工程GBM小鼠肿瘤模型和人GBM组织，我将通过功能表征两种TIME GBM亚型中的血管免疫环境来测试我的假设，并设计特异性和新颖的组合免疫肿瘤学精确治疗策略，增加T细胞浸润和TIMElow GBM中的活性，并抵消TIMEhigh GBM中的免疫抑制性免疫细胞功能。部分重新利用和批准的药物即将获得的结果将有望及时指导未来的试验，以唤起足够的免疫应答并延长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.