INSERM U970, PARCC (Paris Cardiovascular Research Center), Université Paris-Descartes, Sorbonne Paris Cité, Paris, France.
Cancer Res. 2013 Jan 15;73(2):539-49. doi: 10.1158/0008-5472.CAN-12-2325. Epub 2012 Oct 29.
Multitarget antiangiogenic tyrosine kinase inhibitors (TKI) have been shown to reduce regulatory T cells (Treg) in tumor-bearing animals and patients with metastatic renal carcinomas. However, a direct role of the VEGF-A/VEGFR pathway inhibition in this phenomenon is a matter of debate and molecular mechanisms leading to Treg modulation in this setting have not been explored to date. Treg proportion, number, and proliferation were analyzed by flow cytometry in peripheral blood of patients with metastatic colorectal cancer (mCRC) treated with bevacizumab, a monoclonal antibody targeting specifically VEGF-A, and in colon cancer-bearing mice (CT26) treated with drugs targeting the VEGF/VEGFR axis. The direct impact of VEGF-A on Treg induction was assessed together with specific blockade of different isoforms of VEGFRs that may be involved. In CT26-bearing mice, anti-VEGF antibody and sunitinib treatments reduced Treg but masitinib, a TKI not targeting VEGFR, did not. Targeting VEGF-A/VEGFR axis seems sufficient to affect Treg percentages, without any changes in their function. Similarly, bevacizumab inhibited Treg accumulation in peripheral blood of patients with mCRCs. In vitro, Treg expressing VEGFR from tumor-bearing mice directly proliferated in response to VEGF-A. Anti-VEGF-A treatment decreased Treg proliferation in mice as well as in patients with mCRCs. VEGFR-2- but not VEGFR-1-specific blockade led to the same results. We identified a novel mechanism of tumor escape by which VEGF-A directly triggers Treg proliferation. This proliferation is inhibited by VEGF-A/VEGFR-2 blockade. Anti-VEGF-A therapies also have immunologic effects that may be used with a therapeutic goal in the future.
多靶点抗血管生成酪氨酸激酶抑制剂（TKI）已被证明可减少荷瘤动物和转移性肾细胞癌患者中的调节性 T 细胞（Treg）。然而，VEGF-A/VEGFR 通路抑制在这一现象中的直接作用仍存在争议，迄今为止尚未探讨导致这种情况下 Treg 调节的分子机制。通过流式细胞术分析接受贝伐单抗（一种针对 VEGF-A 的单克隆抗体）治疗的转移性结直肠癌（mCRC）患者和接受针对 VEGF/VEGFR 轴的药物治疗的结肠癌荷瘤小鼠（CT26）的外周血中的 Treg 比例、数量和增殖。评估了 VEGF-A 对 Treg 诱导的直接影响，以及针对可能参与其中的不同 VEGFR 异构体的特异性阻断。在 CT26 荷瘤小鼠中，抗 VEGF 抗体和舒尼替尼治疗可减少 Treg，但不针对 VEGFR 的 TKI 马西替尼则没有。靶向 VEGF-A/VEGFR 轴似乎足以影响 Treg 百分比，而不改变其功能。同样，贝伐单抗抑制 mCRC 患者外周血中 Treg 的积聚。在体外，来自荷瘤小鼠的 Treg 直接表达 VEGFR，对 VEGF-A 产生反应而增殖。抗 VEGF-A 治疗可减少小鼠和 mCRC 患者 Treg 的增殖。VEGFR-2 而非 VEGFR-1 的特异性阻断可导致相同的结果。我们发现了一种肿瘤逃避的新机制，即 VEGF-A 直接触发 Treg 增殖。这种增殖可被 VEGF-A/VEGFR-2 阻断抑制。抗 VEGF-A 治疗还具有免疫效应，未来可能用于治疗目的。
