anlotinib alters tumor immune microenvironment by downregulating PD-L1 expression on vascular endothelial cells
anlotinib alters tumor immune microenvironment by downregulating PD-L1 expression on vascular endothelial cells
复制标题
安罗替尼通过下调血管内皮细胞上的 PD-L1 表达来改变肿瘤免疫微环境
DOI：
10.1038/s41419-020-2511-3
复制
发表时间：
2020-05-04
影响因子：
9
通讯作者：
Li, Kai
中科院分区：
文献类型：
--
作者：
Liu, Shaochuan;Qin, Tingting;Li, Kai
异常的血管网是癌症的标志。然而，表达PD-L1的血管内皮细胞（VECs）在肿瘤免疫微环境和抗血管生成治疗中的作用尚不清楚。本研究采用肿瘤患者标本进行免疫组化染色，观察肿瘤标本内PD-L1+CD34+VECs及浸润免疫细胞的数量。采用免疫荧光染色和流式细胞术观察肿瘤组织中CD8+T细胞和FoxP3+T细胞的浸润情况。本研究发现，VECs上PD-L1的表达决定了CD8+T细胞、FoxP3+T细胞的浸润以及肺腺癌患者的预后。Anlotinib通过灭活AKT通路下调VECs上PD-L1的表达，从而提高肿瘤内CD8/FoxP3的比例，重塑免疫微环境。综上所述，我们的研究结果表明，PD-L1在VECs上的高表达抑制了CD8+T细胞的浸润，同时促进了FoxP3+T细胞向肿瘤组织聚集，从而成为“免疫抑制屏障”。Anlotinib可以通过下调VECs上PD-L1的表达来改善免疫微环境，抑制肿瘤生长。
Aberrant vascular network is a hallmark of cancer. However, the role of vascular endothelial cells (VECs)-expressing PD-L1 in tumor immune microenvironment and antiangiogenic therapy remains unclear. In this study, we used the specimens of cancer patients for immunohistochemical staining to observe the number of PD-L1+CD34+VECs and infiltrated immune cells inside tumor specimens. Immunofluorescence staining and flow cytometry were performed to observe the infiltration of CD8+T cells and FoxP3+T cells in tumor tissues. Here, we found that PD-L1 expression on VECs determined CD8+T cells’, FoxP3+T cells’ infiltration, and the prognosis of patients with lung adenocarcinoma. Anlotinib downregulated PD-L1 expression on VECs through the inactivation of AKT pathway, thereby improving the ratio of CD8/FoxP3 inside tumor and remolding the immune microenvironment. In conclusion, our results demonstrate that PD-L1 high expression on VECs inhibits the infiltration of CD8+T cells, whereas promotes the aggregation of FoxP3+T cells into tumor tissues, thus becoming an “immunosuppressive barrier”. Anlotinib can ameliorate the immuno-microenvironment by downregulating PD-L1 expression on VECs to inhibit tumor growth.