anlotinib alters tumor immune microenvironment by downregulating PD-L1 expression on vascular endothelial cells

• Published in: Cell death & disease Vol. 11; no. 5; p. 309
• Main Authors: Liu, Shaochuan, Qin, Tingting, Liu, Zhujun, Wang, Jing, Jia, Yanan, Feng, Yingfang, Gao, Yuan, Li, Kai
• Format: Journal Article
• Language: English
• Published: England Springer Nature B.V 04.05.2020; Nature Publishing Group UK
• Subjects: A549 Cells; Adenocarcinoma; AKT protein; Animals; B7-H1 Antigen - metabolism; CD34 antigen; CD8 antigen; CD8 Antigens - metabolism; Cell Proliferation - drug effects; Down-Regulation - drug effects; Endothelial cells; Female; Flow cytometry; Forkhead Transcription Factors - metabolism; Foxp3 protein; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Immunofluorescence; Indoles - pharmacology; Infiltration; Leukocytes - drug effects; Leukocytes - metabolism; Lung cancer; Lymphocytes; Lymphocytes T; Metastases; Mice, Inbred C57BL; Models, Biological; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - pathology; PD-L1 protein; Prognosis; Proto-Oncogene Proteins c-akt - metabolism; Quinolines - pharmacology; Signal Transduction - drug effects; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology; Up-Regulation - drug effects; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-2511-3

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.