肿瘤细胞治疗研究
英文原题：Immune cell infiltration into brain tumor microenvironment is mediated by Rab27-regulated vascular wall integrity.
侵袭性脑肿瘤常表现出免疫“冷”微环境，其中血管屏障以尚不明确的方式阻碍有效免疫治疗。
侵袭性脑肿瘤常表现出免疫“冷”微环境，其中血管屏障以尚未充分理解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发挥关键作用。在此，我们表明小GTP酶Rab27调控血管形态发生以及对血液成分和免疫效应物的通透性。因此，在Rab27a/b双敲除（Rab27-dKO）小鼠中，脑血管系统异常稀少，而在脑肿瘤（包括同基因胶质母细胞瘤）背景下，血管变得形态异常且高通透。这些缺陷反映在内皮细胞亚群的重排，并伴有静脉内皮亚型的减少以及基因和蛋白表达的变化。值得注意的是，Rab27-dKO脑内皮细胞表现出紧密连接缺陷，从而使其能够使细胞毒性T细胞大规模外渗进入肿瘤团块。我们表明，Rab27调控的血管T细胞浸润可被利用来增强同基因脑肿瘤中的过继性T细胞治疗。
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.
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