Title |
PD-L1 is upregulated by EBV-driven LMP1 through NF-κB pathway and correlates with poor prognosis in natural killer/T-cell lymphoma
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Published in |
Journal of Hematology & Oncology, October 2016
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DOI | 10.1186/s13045-016-0341-7 |
Pubmed ID | |
Authors |
Xi-wen Bi, Hua Wang, Wen-wen Zhang, Jing-hua Wang, Wen-jian Liu, Zhong-jun Xia, Hui-qiang Huang, Wen-qi Jiang, Yu-jing Zhang, Liang Wang |
Abstract |
Natural killer/T-cell lymphoma (NKTCL) is an Epstein-Barr virus (EBV)-associated, highly aggressive lymphoma. Treatment outcome remains sub-optimal, especially for advanced-stage or relapsed diseases. Programmed cell death receptor 1 (PD-1) and PD ligand 1 (PD-L1) have become promising therapeutic targets for various malignancies, but their role in the pathogenesis and their interactions with EBV in NKTCL remains to be investigated. Expression of PD-L1 was measured in NK-92 (EBV-negative) and SNK-6 (EBV-positive) cells by western blot, quantitative real-time PCR and enzyme-linked immunosorbent assay, and flow cytometry, respectively. Latent membrane protein 1 (LMP1)-harboring lentiviral vectors were transfected into NK-92 cells to examine the correlation between LMP1 and PD-L1 expression. Proteins in the downstream pathways of LMP1 signaling were measured in NK-92 cells transfected with LMP1-harboring or negative control vectors as well as in SNK-6 cells. PD-L1 expression on tumor specimens and serum concentration of soluble PD-L1 were collected in a retrospective cohort of patients with Ann Arbor stage I~II NKTCL, and their prognostic significance were analyzed. Expression of PD-L1 was significantly higher in SNK-6 cells than in NK-92 cells, at both protein and mRNA levels. Expression of PD-L1 was remarkably upregulated in NK-92 cells transfected with LMP1-harboring lentiviral vectors compared with those transfected with negative control vectors. Proteins in the MAPK/NF-κB pathway were upregulated in LMP1-expressing NK-92 cells compared with the negative control. Selective inhibitors of those proteins induced significant downregulation of PD-L1 expression in LMP1-expressing NK-92 cells as well as in SNK-6 cells. Patients with a high concentration of serum soluble PD-L1 (≥3.4 ng/ml) or with a high percentage of PD-L1 expression in tumor specimens (≥38 %) exhibited significantly lower response rate to treatment and remarkably worse survival, compared with their counterparts. A high concentration of serum soluble PD-L1 and a high percentage of PD-L1 expression in tumor specimens were independent adverse prognostic factors among patients with stage I~II NKTCL. PD-L1 expression positively correlated LMP1 expression in NKTCL, which was probably mediated by the MAPK/NF-κB pathway. PD-L1 expression in serum and tumor tissues has significant prognostic value for early-stage NKTCL. |
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Country | Count | As % |
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Spain | 1 | <1% |
Unknown | 103 | 99% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Bachelor | 17 | 16% |
Student > Ph. D. Student | 15 | 14% |
Student > Master | 11 | 11% |
Researcher | 9 | 9% |
Student > Doctoral Student | 5 | 5% |
Other | 18 | 17% |
Unknown | 29 | 28% |
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Immunology and Microbiology | 5 | 5% |
Agricultural and Biological Sciences | 4 | 4% |
Nursing and Health Professions | 3 | 3% |
Other | 9 | 9% |
Unknown | 35 | 34% |