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

Cell Death Dis. 2020 May 4;11(5):309. doi: 10.1038/s41419-020-2511-3.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • B7-H1 Antigen / metabolism*
  • CD8 Antigens / metabolism
  • Cell Proliferation / drug effects
  • Down-Regulation* / drug effects
  • Female
  • Forkhead Transcription Factors / metabolism
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Indoles / pharmacology*
  • Leukocytes / drug effects
  • Leukocytes / metabolism
  • Mice, Inbred C57BL
  • Models, Biological
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • 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

Substances

  • B7-H1 Antigen
  • CD8 Antigens
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Indoles
  • Quinolines
  • Vascular Endothelial Growth Factor A
  • anlotinib
  • Proto-Oncogene Proteins c-akt