VEGF Neutralization Plus CTLA-4 Blockade Alters Soluble and Cellular Factors Associated with Enhancing Lymphocyte Infiltration and Humoral Recognition in Melanoma.
VEGF Neutralization Plus CTLA-4 Blockade Alters Soluble and Cellular Factors Associated with Enhancing Lymphocyte Infiltration and Humoral Recognition in Melanoma.
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DOI：
10.1158/2326-6066.cir-16-0084
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发表时间：
2016-10
影响因子：
10.1
通讯作者：
Hodi FS
中科院分区：
文献类型：
--
作者：
Wu X;Giobbie-Hurder A;Liao X;Lawrence D;McDermott D;Zhou J;Rodig S;Hodi FS
特异性细胞毒性淋巴细胞对肿瘤靶点的免疫识别对于肿瘤的有效排斥是必不可少的。在转移性黑色素瘤患者中，ipilimumab(一种阻断CTLA-4功能的抗体)与贝伐单抗(一种抑制血管生成的抗体)联合使用的I期临床试验发现，良好的临床结果与肿瘤内皮细胞激活和淋巴细胞浸润增加有关。为了更好地理解潜在的机制，我们寻找了随着患者治疗而改变的特征和因素。Ipilimumab联合贝伐单抗(ipi-Bev)可增加肿瘤血管ICAM-1和VCAM-1的表达。治疗还改变了许多循环细胞因子和趋化因子的浓度，包括IP-10、IL-1α、肿瘤坏死因子α、GRO、干扰素α2和IL 8的升高，而大多数患者的血管内皮生长因子-A降低。IL-1α和肿瘤坏死因子α在体外诱导黑色素瘤相关内皮细胞表达E-选择素、细胞间黏附分子-1和血管细胞间黏附分子-1，并促进活化T细胞与其黏附。血管内皮生长因子-A抑制肿瘤坏死因子α诱导的细胞间黏附分子-1和血管细胞间黏附分子-1的表达及T细胞黏附，贝伐单抗可阻断该作用。IP-10在体外促进T细胞通过TEC的迁移，经常在黑色素瘤细胞中表达，并在接受治疗的患者的肿瘤亚群中上调。IP-10在肿瘤中的强劲上调伴随着T细胞浸润的增加。IPI-Bev还增强了识别黑色素瘤、肿瘤内皮和肿瘤间充质干细胞靶点的体液免疫反应。我们的研究结果表明，IPI-Bev治疗通过增强淋巴细胞渗透和抗体反应，增强了肿瘤微环境中的免疫识别。白介素1α、肿瘤坏死因子α和IP-10与血管内皮生长因子中和一起参与了IPI-Bev诱导的黑色素瘤免疫识别。
Immune recognition of tumor targets by specific cytotoxic lymphocytes is essential for the effective rejection of tumors. A phase I clinical trial of ipilimumab (an antibody that blocks CTLA-4 function) in combination with bevacizumab (an antibody that inhibits angiogenesis) in patients with metastatic melanoma found favorable clinical outcomes were associated with increased tumor endothelial activation and lymphocyte infiltration. To better understand the underlying mechanisms, we sought features and factors that changed as a function of treatment in patients. Ipilimumab plus bevacizumab (Ipi-Bev) increased tumor vascular expression of ICAM-1 and VCAM-1. Treatment also altered concentrations of many circulating cytokines and chemokines, including increases of IP-10, IL1α, TNFα, GRO, IFNα2, and IL8, with decreases in VEGF-A in most patients. IL1α and TNFα induced expression of E-selectin, ICAM-1, and VCAM-1 on melanoma tumor-associated endothelial cells (TEC) in vitro and promoted adhesion of activated T cells onto TEC. VEGF-A inhibited TNFα-induced expression of ICAM-1 and VCAM-1 and T-cell adhesion, which was blocked by bevacizumab. IP-10 promoted T-cell migration across TEC in vitro, was frequently expressed by melanoma cells, and was upregulated in a subset of tumors in treated patients. Robust upregulation of IP-10 in tumors was accompanied by increased T-cell infiltration. Ipi-Bev also augmented humoral immune responses recognizing targets in melanoma, tumor endothelial, and tumor mesenchymal stem cells. Our findings suggest that Ipi-Bev therapy augments immune recognition in the tumor microenvironment through enhancing lymphocyte infiltration and antibody responses. IL1α, TNFα, and IP-10, together with VEGF neutralization, contribute to Ipi-Bev–induced melanoma immune recognition.