Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Clin Cancer Res. 2017 Jan 15;23(2):587-599. doi: 10.1158/1078-0432.CCR-16-0387. Epub 2016 Jul 11.
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.
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.
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.
VEGF expression in ovarian cancer induced MDSCs, inhibited local immunity, and contributed to poor prognosis. Clin Cancer Res; 23(2); 587-99. ©2016 AACR.
卵巢癌中 VEGFA 的高表达是一个不利的预后因素。然而，VEGF 在肿瘤免疫中的作用仍不清楚。在这里，我们研究了 VEGF 对卵巢癌局部免疫的影响，包括对髓系来源的抑制细胞（MDSC）的诱导。
通过基因表达微阵列和免疫组化分析高级别浆液性卵巢癌（HGSOC）病例中 VEGF、CD8 和 CD33 的表达。在小鼠模型中分析 MDSC 上 VEGFR1 和 VEGFR2 的表达水平，并研究 VEGF-A 对 MDSC 扩增的直接作用。在对照肿瘤和来源于靶向 Vegf-a 的短发夹 RNA 细胞的肿瘤中分析 Gr1 MDSC 和淋巴细胞频率。此外，还研究了抗 Gr-1 抗体的治疗效果。
微阵列分析显示，在 VEGF 高表达的病例中，几种髓样细胞趋化因子的表达上调，与淋巴细胞相关途径的表达下调。在免疫组化分析中，腹腔播散中的 VEGF 表达与 MDSC 浸润相关。MDSC 浸润高的病例，与肿瘤内 CD8 T 细胞浸润呈负相关，总生存时间较短。在小鼠模型中，肿瘤内 MDSC 表达 VEGFR1 和 VEGFR2。VEGF 信号增强了 MDSC 的迁移和分化。肿瘤细胞中 Vegf-a 的敲低导致 MDSC 浸润减少和 CD8 T 细胞浸润增加。此外，抗 Gr-1 抗体治疗延迟了对照肿瘤的生长，而 Vegf-a 敲低肿瘤不受抗 Gr-1 抗体治疗的影响。
卵巢癌中 VEGFA 的表达诱导 MDSC，抑制局部免疫，并导致不良预后。Clin Cancer Res; 23(2); 587-99. ©2016 AACR.
