Adnani Lata, Meehan Brian, Kim Minjun, Choi Dongsic, Rudd Christopher E, Riazalhosseini Yasser, Rak Janusz
Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
Victor Phillip Dahdaleh Institute of Genomic Medicine at McGill University. McGill University Department of Human Genetics, Montreal, QC, Canada.
Sci Adv. 2025 May 23;11(21):eadr6940. doi: 10.1126/sciadv.adr6940.
Aggressive brain tumors often exhibit immunologically 'cold' microenvironment, where the vascular barrier impedes effective immunotherapy in poorly understood ways. Tumor vasculature also plays a pivotal role in immunoregulation and antitumor immunity. Here, we show that small GTPase Rab27 controls the vascular morphogenesis and permeability for blood content and immune effectors. Thus, in Rab27a/b double knock out (Rab27-dKO) mice, the brain vasculature is abnormally scarce, while the blood vessels become dysmorphic and hyperpermeable in the context of brain tumors, including syngeneic glioblastoma. These defects are reflected in rearrangements of endothelial cell subpopulations with underlying diminution of venous endothelial subtype along with changes in gene and protein expression. Notably, Rab27-dKO brain endothelial cells exhibit deficient tight junctions, whereby they enable large-scale extravasation of cytotoxic T cells into the tumor mass. We show that Rab27-regulated vascular T cell infiltration can be exploited to enhance adoptive T cell therapy in syngeneic brain tumors.
侵袭性脑肿瘤通常表现出免疫“冷”微环境，其中血管屏障以尚不清楚的方式阻碍有效的免疫治疗。肿瘤血管系统在免疫调节和抗肿瘤免疫中也起着关键作用。在此，我们表明小GTP酶Rab27控制血管形态发生以及血液成分和免疫效应器的通透性。因此，在Rab27a/b双敲除（Rab27-dKO）小鼠中，脑脉管系统异常稀少，而在包括同基因胶质母细胞瘤在内的脑肿瘤情况下，血管变得畸形且通透性增加。这些缺陷反映在内皮细胞亚群的重排中，静脉内皮亚型的数量减少，同时基因和蛋白质表达发生变化。值得注意的是，Rab27-dKO脑内皮细胞表现出紧密连接缺陷，从而使细胞毒性T细胞能够大规模渗入肿瘤块。我们表明，Rab27调节的血管T细胞浸润可用于增强同基因脑肿瘤的过继性T细胞治疗。
