Optimized antiangiogenic reprogramming of the tumor microenvironment potentiates CD40 immunotherapy
Optimized antiangiogenic reprogramming of the tumor microenvironment potentiates CD40 immunotherapy
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DOI：
10.1073/pnas.1902145116
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发表时间：
2020-01-07
影响因子：
11.1
通讯作者：
Zippelius, Alfred
中科院分区：
文献类型：
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作者：
Kashyap, Abhishek S.;Schmittnaegel, Martina;Zippelius, Alfred
癌症免疫疗法越来越多地与靶向疗法相结合，以改善治疗效果。我们发现，激动性抗CD 40与靶向2种促血管生成因子（血管内皮生长因子A（VEGFA）和血管生成素2（Ang 2/ANGPT 2））的抗血管生成抗体的组合诱导了多效免疫机制，促进了几种肿瘤模型中的肿瘤排斥反应。一方面，VEGFA/Ang 2阻断诱导肿瘤微血管的消退，同时降低未灌注血管的比例并减少剩余血管的渗漏。另一方面，抗VEGFA/Ang 2和抗CD 40均独立地促进促炎性巨噬细胞偏斜并增加肿瘤微环境中的树突状细胞活化，这在2种治疗组合后进一步放大。最后，联合治疗引起肿瘤中细胞毒性CD 8（+）T细胞的快速浸润和瘤内重新分布，这主要是由Ang 2阻断驱动的。总的来说，这些非冗余的协同机制赋予T细胞改善的效应子功能，有助于更有效地控制肿瘤，强调了抗血管生成免疫疗法在癌症中的治疗潜力。
Cancer immunotherapies are increasingly combined with targeted therapies to improve therapeutic outcomes. We show that combination of agonistic anti-CD40 with antiangiogenic antibodies targeting 2 proangiogenic factors, vascular endothelial growth factor A (VEGFA) and angiopoietin 2 (Ang2/ANGPT2), induces pleiotropic immune mechanisms that facilitate tumor rejection in several tumor models. On the one hand, VEGFA/Ang2 blockade induced regression of the tumor microvasculature while decreasing the proportion of nonperfused vessels and reducing leakiness of the remaining vessels. On the other hand, both anti-VEGFA/Ang2 and anti-CD40 independently promoted proinflammatory macrophage skewing and increased dendritic cell activation in the tumor microenvironment, which were further amplified upon combination of the 2 treatments. Finally, combined therapy provoked brisk infiltration and intratumoral redistribution of cytotoxic CD8(+) T cells in the tumors, which was mainly driven by Ang2 blockade. Overall, these nonredundant synergistic mechanisms endowed T cells with improved effector functions that were conducive to more efficient tumor control, underscoring the therapeutic potential of antiangiogenic immunotherapy in cancer.