RRC ID 65462
Author Horikawa N, Abiko K, Matsumura N, Hamanishi J, Baba T, Yamaguchi K, Yoshioka Y, Koshiyama M, Konishi I.
Title Expression of Vascular Endothelial Growth Factor in Ovarian Cancer Inhibits Tumor Immunity through the Accumulation of Myeloid-Derived Suppressor Cells.
Journal Clin Cancer Res
Abstract PURPOSE:High VEGF expression in ovarian cancer is an unfavorable prognostic factor. However, the role of VEGF in tumor immunity remains unclear. Here, we examined the impact of VEGF on local immunity, including induction of myeloid-derived suppressor cells (MDSC), in ovarian cancer.
EXPERIMENTAL DESIGN:High-grade serous ovarian cancer (HGSOC) cases were analyzed by gene expression microarray and IHC for VEGF, CD8, and CD33. VEGF receptor (VEGFR) 1 and VEGFR2 expression levels on MDSCs were analyzed in a mouse model, and the direct effects of VEGF-A on MDSC expansion were investigated. Gr1+ MDSCs and lymphocyte frequencies were analyzed in control tumors and tumors derived from cells harboring short hairpin RNA targeting Vegf-a. In addition, the therapeutic effects of anti-Gr-1 antibodies were examined.
RESULTS:Microarray analysis revealed the upregulation of several myeloid cell chemoattractants and the downregulation of lymphocyte-related pathways in cases with high VEGF expression. In immunohistochemical analysis, VEGF expression in peritoneal dissemination correlated with MDSC infiltration. Cases with high MDSC infiltration, which was inversely correlated with intratumoral CD8+ T-cell infiltration, exhibited shorter overall survival. In a mouse model, intratumoral MDSCs expressed both VEGFR1 and VEGFR2. MDSC migration and differentiation were augmented by VEGF signaling. Vegf-a knockdown in tumor cells resulted in decreased MDSC infiltration and increased CD8+ T-cell infiltration. Moreover, treatment with anti-Gr-1 antibodies delayed the growth of control tumors, whereas Vegf-a-knockdown tumors were unaffected by anti-Gr-1 antibody treatment.
CONCLUSIONS:VEGF expression in ovarian cancer induced MDSCs, inhibited local immunity, and contributed to poor prognosis. Clin Cancer Res; 23(2); 587-99. ©2016 AACR.
Volume 23(2)
Pages 587-599
Published 2017-1-15
DOI 10.1158/1078-0432.CCR-16-0387
PII 1078-0432.CCR-16-0387
PMID 27401249
MeSH Animals Cell Differentiation / genetics Cell Movement / genetics Female Gene Expression Regulation, Neoplastic Humans Immunity / genetics Lymphocytes, Tumor-Infiltrating / immunology Lymphocytes, Tumor-Infiltrating / pathology Mice Microarray Analysis Myeloid Cells / immunology Myeloid Cells / pathology Ovarian Neoplasms / genetics* Ovarian Neoplasms / immunology Ovarian Neoplasms / pathology Signal Transduction Vascular Endothelial Growth Factor A / genetics* Vascular Endothelial Growth Factor Receptor-1 / genetics* Vascular Endothelial Growth Factor Receptor-2 / genetics* Xenograft Model Antitumor Assays
IF 10.107
Human and Animal Cells OV2944-HM-1(RCB1483)