Targeting VEGFR2 with Ramucirumab strongly impacts effector/ activated regulatory T cells and CD8+ T cells in the tumor microenvironment

• DOI: 10.1186/s40425-018-0403-1
• Publication Date: 2018-10-11T14:41:36Z
• Authors: Yasuko Tada; Yosuke Togashi; Daisuke Kotani; Takeshi Kuwata; Eichi Sato; Akihito Kawazoe; Toshihiko Doi; Hisashi Wada; Hiroyoshi Nishikawa; Kohei Shitara
• Keywords: Male; 0301 basic medicine; Programmed Cell Death 1 Receptor; Antineoplastic Agents; CD8-Positive T-Lymphocytes; Antibodies, Monoclonal, Humanized; T-Lymphocytes, Regulatory; Ramucirumab; 03 medical and health sciences; Stomach Neoplasms; PD-1; Tumor Microenvironment; Humans; RC254-282; Aged; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Antibodies, Monoclonal; Regulatory T cells; Middle Aged; Vascular Endothelial Growth Factor Receptor-2; 3. Good health; VEGFR2; Female; Gastric cancer; Research Article

Several studies have established a correlation between the VEGF-VEGFR2 axis and an immunosuppressive microenvironment; this immunosuppression can be overcome by anti-angiogenic reagents, such as ramucirumab (RAM). However, little is known about the immunological impact of anti-angiogenic reagents within the tumor microenvironment in human clinical samples. This study aimed at investigating the effects of RAM on the tumor microenvironmental immune status in human cancers.We prospectively enrolled 20 patients with advanced gastric cancer (GC) who received RAM-containing chemotherapy. We obtained paired samples from peripheral blood mononuclear cells (PBMCs) and tumor-infiltrating lymphocytes (TILs) in primary tumors both pre- and post-RAM therapy to assess immune profiles by immunohistochemistry and flow cytometry.Within the tumor microenvironment, both PD-L1 expression and CD8+ T-cell infiltration increased after RAM-containing therapies. In addition, CD45RA-FOXP3highCD4+ cells (effector regulatory T cells [eTreg cells]) and PD-1 expression by CD8+ T cells were significantly reduced in TILs compared with PBMCs after RAM-containing therapies. Patients with partial response and longer progression-free survival had significantly higher pre-treatment eTreg frequencies in TILs than those with progressive disease. In in vitro analysis, VEGFR2 was highly expressed by eTreg cells. Further, VEGFA promoted VEGFR2+ eTreg cell proliferation, and this effect could be inhibited by RAM.This study suggests that the frequency of eTreg cells in TILs could be a biomarker for stratifying clinical responses to RAM-containing therapies. Further, we propose that RAM may be employed as an immuno-modulator in combination with immune checkpoint blockade.