Local endothelial complement activation reverses endothelial quiescence, enabling t-cell homing, and tumor control during t-cell immunotherapy.
Local endothelial complement activation reverses endothelial quiescence, enabling t-cell homing, and tumor control during t-cell immunotherapy.
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DOI：
10.1080/2162402x.2017.1326442
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发表时间：
2017
期刊：
影响因子：
7.2
通讯作者：
Coukos G
中科院分区：
文献类型：
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作者：
Facciabene A;De Sanctis F;Pierini S;Reis ES;Balint K;Facciponte J;Rueter J;Kagabu M;Magotti P;Lanitis E;DeAngelis RA;Buckanovich RJ;Song WC;Lambris JD;Coukos G
癌症免疫疗法依赖于T细胞浸润肿瘤的能力。内皮构成了肿瘤和效应T细胞之间的屏障，操纵局部血管渗透性的能力可以转化为有效的免疫疗法。在这里，我们表明，在过继性T细胞治疗的背景下，以足够高的剂量递送的抗肿瘤T细胞可以克服内皮屏障并浸润肿瘤，这一过程需要局部产生C3，肿瘤内皮上的补体激活和C5a的释放。反过来，C5a作用于内皮细胞，促进粘附分子的上调和T细胞归巢。C3或C5a受体1（C5aR1）的基因缺失和C5aR1的药理学阻断，削弱了T细胞克服内皮屏障、浸润肿瘤和控制体内肿瘤进展的能力，而遗传嵌合体小鼠表明，肿瘤基质而不是白细胞表达的C3和C5aR1支配T细胞归巢，作用于局部内皮。在体外，内皮细胞C3和C5a的表达所需的内皮细胞活化1型细胞因子。我们的数据表明，有效的免疫治疗是T细胞响应局部补体激活而成功归巢的结果，从而破坏了肿瘤内皮屏障。
Cancer immunotherapy relies upon the ability of T cells to infiltrate tumors. The endothelium constitutes a barrier between the tumor and effector T cells, and the ability to manipulate local vascular permeability could be translated into effective immunotherapy. Here, we show that in the context of adoptive T cell therapy, antitumor T cells, delivered at high enough doses, can overcome the endothelial barrier and infiltrate tumors, a process that requires local production of C3, complement activation on tumor endothelium and release of C5a. C5a, in turn, acts on endothelial cells promoting the upregulation of adhesion molecules and T-cell homing. Genetic deletion of C3 or the C5a receptor 1 (C5aR1), and pharmacological blockade of C5aR1, impaired the ability of T cells to overcome the endothelial barrier, infiltrate tumors, and control tumor progression in vivo, while genetic chimera mice demonstrated that C3 and C5aR1 expression by tumor stroma, and not leukocytes, governs T cell homing, acting on the local endothelium. In vitro, endothelial C3 and C5a expressions were required for endothelial activation by type 1 cytokines. Our data indicate that effective immunotherapy is a consequence of successful homing of T cells in response to local complement activation, which disrupts the tumor endothelial barrier.