LPA4-Mediated Vascular Network Formation Increases the Efficacy of Anti-PD-1 Therapy against Brain Tumors
LPA4-Mediated Vascular Network Formation Increases the Efficacy of Anti-PD-1 Therapy against Brain Tumors
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DOI：
10.1158/0008-5472.can-18-0498
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发表时间：
2018-12-01
期刊：
影响因子：
11.2
通讯作者：
Takakura, Nobuyuki
中科院分区：
文献类型：
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作者：
Eino, Daisuke;Tsukada, Yohei;Takakura, Nobuyuki
肿瘤血管的结构和功能深刻影响着肿瘤微环境。通过溶血磷脂酸受体4（LPA 4）介导的信号促进血管网络形成，以恢复皮下肿瘤中的正常血管屏障功能，从而改善药物递送。然而，血管系统的特征因器官和肿瘤类型而异，并且在不同癌症中LPA对血管功能的修饰如何影响药物递送和白细胞运输尚不清楚。在这里，我们表明LPA 4激活促进脑肿瘤中精细血管结构的形成。RhoA/ROCK信号通路促进LPA诱导的内皮细胞-细胞粘附，并且LPA 4刺激后RhoA/ROCK活性调节VCAM-1的表达。这导致淋巴细胞浸润到肿瘤中增加。LPA改善了外源性IgG向脑肿瘤中的递送，并增强了抗程序性细胞死亡-1抗体疗法的抗癌效果。这些结果表明，LPA对血管结构和功能的影响不仅适用于化疗，但也immunotherapy.Significance：这些研究结果表明，溶血磷脂酸，脂质介质，促进脑肿瘤中的细毛细血管网络的发展，诱导收紧内皮细胞与细胞粘附，促进改善药物输送，淋巴细胞渗透。(C)2018年AACR。
The structure and function of tumor blood vessels profoundly affects the tumor microenvironment. Signals mediated through the lysophosphatidic acid receptor 4 (LPA4) promote vascular network formation to restore normal vascular barrier function in subcutaneous tumors and thus improve drug delivery. However, the characteristics of the vasculature vary by organ and tumor types, and how drug delivery and leukocyte trafficking are affected by modification of vascular function by LPA in different cancers is unclear. Here, we show that LPA4 activation promotes the formation of fine vascular structures in brain tumors. RhoA/ROCK signaling contributed to LPA-induced endothelial cell-cell adhesion, and RhoA/ROCK activity following LPA4 stimulation regulated expression of VCAM-1. This resulted in increased lymphocyte infiltration into the tumor. LPA improved delivery of exogenous IgG into brain tumors and enhanced the anticancer effect of anti-programmed cell death-1 antibody therapy. These results indicate the effects of LPA on vascular structure and function apply not only to chemotherapy but also to immunotherapy.Significance: These findings demonstrate that lysophosphatidic acid, a lipid mediator, promotes development of a fine capillary network in brain tumors by inducing tightening of endothelial cell-to-cell adhesion, facilitating improved drug delivery, and lymphocyte penetration. (C) 2018 AACR.