Transcriptional regulation of VEGFA expression in T-regulatory cells from breast cancer patients

• DOI: 10.1007/s00262-020-02808-0
• Publication Date: 2021-01-04T05:03:07Z
• Authors: Kirti Kajal; Sayantan Bose; Abir K. Panda; Dwaipayan Chakrab...; Sreeparna Chakrab...; Subhadip Pati; Tania Sarkar; Subhanki Dhar; Dia Roy; Shilpi Saha; Gaurisankar Sa
• Keywords: STAT3 Transcription Factor; Vascular Endothelial Growth Factor A; 0301 basic medicine; Mice, Inbred BALB C; Neovascularization, Pathologic; Endothelial Cells; Apoptosis; Breast Neoplasms; Prognosis; T-Lymphocytes, Regulatory; Xenograft Model Antitumor Assays; 3. Good health; Gene Expression Regulation, Neoplastic; Mice; 03 medical and health sciences; Case-Control Studies; Biomarkers, Tumor; Tumor Cells, Cultured; Animals; Humans; Female; Cell Proliferation

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.