Kajal Kirti, Bose Sayantan, Panda Abir K, Chakraborty Dwaipayan, Chakraborty Sreeparna, Pati Subhadip, Sarkar Tania, Dhar Subhanki, Roy Dia, Saha Shilpi, Sa Gaurisankar
Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata, 700 054, India.
Cancer Immunol Immunother. 2021 Jul;70(7):1877-1891. doi: 10.1007/s00262-020-02808-0. Epub 2021 Jan 4.
The initiation of new blood vessel formation (neo-angiogenesis) is one of the primary requirements for the establishment of tumor. As the tumor grows beyond a certain size, a hypoxic-condition arises in the inner core of tumor, triggering the release of chemokines, which attract T-regulatory (Treg) cells in the tumor-site. The presence of FOXP3, a lineage-specific transcription factor, expressing Treg cells in various types of tumor implements immunosuppressive and tumor-promoting strategies. One such strategy is the invitation of endothelial cells for neo-vascularization in the tumor site. Here we report that as the disease progresses, Treg cells from breast cancer patients are capable of secreting high-amount of VEGFA. The VEGFA promoter lacks Treg-specific transcription factor FOXP3 binding site. FOXP3 in association with locus-specific transcription factor STAT3 binds to VEGFA promoter to induce its transcription in Treg cells obtained from breast cancer patients. Treg cell-secreted VEGFA induces neo-angiogenesis from endothelial cells under in-vitro conditions. Targeting Tregs in mice with breast tumor reduces tumor growth as well as the level of neo-angiogenesis in the tumor tissue.
新血管形成（新生血管生成）的启动是肿瘤形成的主要条件之一。随着肿瘤生长超过一定大小，肿瘤内部核心会出现缺氧状态，从而触发趋化因子的释放，这些趋化因子会吸引肿瘤部位的调节性T细胞（Treg细胞）。叉头框蛋白3（FOXP3）作为一种谱系特异性转录因子，在各类肿瘤中表达Treg细胞，其存在实施免疫抑制和促进肿瘤生长的策略。其中一种策略是促使内皮细胞在肿瘤部位进行新生血管化。在此我们报告，随着疾病进展，乳腺癌患者的Treg细胞能够分泌大量血管内皮生长因子A（VEGFA）。VEGFA启动子缺乏Treg特异性转录因子FOXP3结合位点。FOXP3与位点特异性转录因子信号转导与转录激活因子3（STAT3）结合，进而与VEGFA启动子结合，以诱导其在乳腺癌患者来源的Treg细胞中进行转录。Treg细胞分泌的VEGFA在体外条件下可诱导内皮细胞进行新生血管生成。在患有乳腺肿瘤的小鼠中靶向Treg细胞可减少肿瘤生长以及肿瘤组织中的新生血管生成水平。
