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Anti-VEGF Treatment Enhances CD8+ T-Cell Antitumor Activity by Amplifying Hypoxia.

抗 VEGF 处理通过放大缺氧增强 CD8 + T 细胞抗肿瘤活性。

  • 影响因子:8.58
  • DOI:10.1158/2326-6066.CIR-19-0360
  • 作者列表:"de Almeida PE","Mak J","Hernandez G","Jesudason R","Herault A","Javinal V","Borneo J","Kim JM","Walsh KB
  • 发表时间:2020-04-01
Abstract

:Anti-angiogenic therapies that target the vascular endothelial growth factor (VEGF) pathway have been used clinically to combat cancer for over a decade. Beyond having a direct impact on blood vessel development and tumor perfusion, accumulating evidence indicates that these agents also affect antitumor immune responses. Numerous clinical trials combining anti-angiogenic drugs with immunotherapies for the treatment of cancer are ongoing, but a mechanistic understanding of how disruption of tumor angiogenesis may impact immunity is not fully discerned. Here we reveal that blockade of VEGF-A with a monoclonal antibody to VEGF augments activation of CD8+ T cells within tumors and potentiates their capacity to produce cytokines. We demonstrate that this phenomenon relies on the disruption of VEGFR2 signaling in the tumor microenvironment, but does not affect CD8+ T cells directly. Instead, the augmented functional capacity of CD8+ T cells stems from increased tumor hypoxia that initiates a hypoxia-inducible factor-1α (HIF-1α) program within CD8+ T cells that directly enhances cytokine production. Lastly, combinatorial administration of anti-VEGF with an immunotherapeutic antibody, anti-OX40, improved antitumor activity over single-agent treatments. Our findings illustrate that anti-VEGF treatment enhances CD8+ T-cell effector function and provides a mechanistic rationale for combining anti-angiogenic and immunotherapeutic drugs for cancer treatment.

摘要

: 靶向血管内皮生长因子 (VEGF) 通路的抗血管生成疗法已在临床上用于对抗癌症超过十年。除了对血管发育和肿瘤灌注有直接影响之外,越来越多的证据表明这些药物也影响抗肿瘤免疫反应。许多临床试验将抗血管生成药物与免疫疗法结合用于治疗癌症,但对肿瘤血管生成的破坏如何影响免疫的机制理解尚未完全明确。在这里,我们揭示了用 VEGF 单克隆抗体阻断 VEGF-A 可增强肿瘤内 CD8 + T 细胞的活化,增强其产生细胞因子的能力。我们证明这种现象依赖于肿瘤微环境中 VEGFR2 信号的破坏,但不直接影响 CD8 + T 细胞。相反,CD8 + T 细胞增强的功能能力源于肿瘤缺氧增加,在 CD8 + T 细胞内启动缺氧诱导因子-1 α (hif-1 α) 程序,直接增强细胞因子的产生。最后,抗 VEGF 与免疫治疗性抗体 anti-OX40 的组合给药比单药治疗提高了抗肿瘤活性。我们的研究结果表明,抗 VEGF 治疗增强了 CD8 + T 细胞效应功能,并为联合抗血管生成和免疫治疗药物用于癌症治疗提供了机制理论基础。

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