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

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.

SUBMITTER: Liu S

PROVIDER: S-EPMC7198575 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Liu Shaochuan S Qin Tingting T Liu Zhujun Z Wang Jing J Jia Yanan Y Feng Yingfang Y Gao Yuan Y Li Kai K

Cell death & disease 20200504 5

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<sup>+</sup> CD34<sup>+</sup> VECs and infiltrated immune cells inside tumor specimens. Immunofluorescence staining and flow cytometry were performed to observe the infiltration of ...[more]

PMID: 32366856

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Project description:BACKGROUND:PD-L1 is an immune inhibitory receptor ligand that leads to T cell dysfunction and apoptosis by binding to its receptor PD-1, which works in braking inflammatory response and conspiring tumor immune evasion. However, in gliomas, the cause of PD-L1 expression in the tumor microenvironment is not yet clear. Besides, auxiliary biomarkers are urgently needed for screening possible responsive glioma patients for anti-PD-1/PD-L1 therapies. METHODS:The distribution of tumor-infiltrating T cells and PD-L1 expression was analyzed via immunofluorescence in orthotopic murine glioma model. The expression of PD-L1 in immune cell populations was detected by flow cytometry. Data excavated from TCGA LGG/GBM datasets and the Ivy Glioblastoma Atlas Project was used for in silico analysis of the correlation among genes and survival. RESULTS:The distribution of tumor-infiltrating T cells and PD-L1 expression, which parallels in murine orthotopic glioma model and human glioma microdissections, was interrelated. The IFN-? level was positively correlated with PD-L1 expression in murine glioma. Further, IFN-? induces PD-L1 expression on primary cultured microglia, bone marrow-derived macrophages, and GL261 glioma cells in vitro. Seven IFN-?-induced genes, namely GBP5, ICAM1, CAMK2D, IRF1, SOCS3, CD44, and CCL2, were selected to calculate as substitute indicator for IFN-? level. By combining the relative expression of the listed IFN-?-induced genes, IFN-? score was positively correlated with PD-L1 expression in different anatomic structures of human glioma and in glioma of different malignancies. CONCLUSION:Our study identified the distribution of tumor-infiltrating T cells and PD-L1 expression in murine glioma model and human glioma samples. And we found that IFN-? is an important cause of PD-L1 expression in the glioma microenvironment. Further, we proposed IFN-? score aggregated from the expressions of the listed IFN-?-induced genes as a complementary prognostic indicator for anti-PD-1/PD-L1 therapy.

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

Publications

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

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