PD-L1 is upregulated by EBV-driven LMP1 through NF-κB pathway and correlates with poor prognosis in natural killer/T-cell lymphoma
Abstract Background 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 pro...
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| Format: | Article |
| Language: | English |
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BMC
2016-10-01
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| Series: | Journal of Hematology & Oncology |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13045-016-0341-7 |
| _version_ | 1818541500685877248 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Xi-wen Bi |
| collection | DOAJ |
| description | Abstract Background 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. Methods 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. Results 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. Conclusions 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. |
| first_indexed | 2024-12-11T22:10:06Z |
| format | Article |
| id | doaj.art-6d8ba534587b4011b112f1e51a60483f |
| institution | Directory Open Access Journal |
| issn | 1756-8722 |
| language | English |
| last_indexed | 2024-12-11T22:10:06Z |
| publishDate | 2016-10-01 |
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| series | Journal of Hematology & Oncology |
| spelling | doaj.art-6d8ba534587b4011b112f1e51a60483f2022-12-22T00:48:49ZengBMCJournal of Hematology & Oncology1756-87222016-10-019111210.1186/s13045-016-0341-7PD-L1 is upregulated by EBV-driven LMP1 through NF-κB pathway and correlates with poor prognosis in natural killer/T-cell lymphomaXi-wen Bi0Hua Wang1Wen-wen Zhang2Jing-hua Wang3Wen-jian Liu4Zhong-jun Xia5Hui-qiang Huang6Wen-qi Jiang7Yu-jing Zhang8Liang Wang9Department of Hematologic Oncology, State Key Laboratory of Oncology in South China/Cancer Center, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen UniversityDepartment of Hematologic Oncology, State Key Laboratory of Oncology in South China/Cancer Center, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen UniversityDepartment of Hematologic Oncology, State Key Laboratory of Oncology in South China/Cancer Center, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen UniversityDepartment of Hematologic Oncology, State Key Laboratory of Oncology in South China/Cancer Center, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen UniversityDepartment of Hematologic Oncology, State Key Laboratory of Oncology in South China/Cancer Center, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen UniversityDepartment of Hematologic Oncology, State Key Laboratory of Oncology in South China/Cancer Center, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen UniversityDepartment of Hematologic Oncology, State Key Laboratory of Oncology in South China/Cancer Center, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen UniversityDepartment of Hematologic Oncology, State Key Laboratory of Oncology in South China/Cancer Center, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen UniversityDepartment of Hematologic Oncology, State Key Laboratory of Oncology in South China/Cancer Center, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen UniversityDepartment of Hematologic Oncology, State Key Laboratory of Oncology in South China/Cancer Center, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen UniversityAbstract Background 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. Methods 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. Results 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. Conclusions 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.http://link.springer.com/article/10.1186/s13045-016-0341-7Natural killer/T-cell lymphomaLatent membrane protein 1Epstein–Barr virusProgrammed cell death receptor 1 |
| spellingShingle | 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 PD-L1 is upregulated by EBV-driven LMP1 through NF-κB pathway and correlates with poor prognosis in natural killer/T-cell lymphoma Journal of Hematology & Oncology Natural killer/T-cell lymphoma Latent membrane protein 1 Epstein–Barr virus Programmed cell death receptor 1 |
| title | PD-L1 is upregulated by EBV-driven LMP1 through NF-κB pathway and correlates with poor prognosis in natural killer/T-cell lymphoma |
| title_full | PD-L1 is upregulated by EBV-driven LMP1 through NF-κB pathway and correlates with poor prognosis in natural killer/T-cell lymphoma |
| title_fullStr | PD-L1 is upregulated by EBV-driven LMP1 through NF-κB pathway and correlates with poor prognosis in natural killer/T-cell lymphoma |
| title_full_unstemmed | PD-L1 is upregulated by EBV-driven LMP1 through NF-κB pathway and correlates with poor prognosis in natural killer/T-cell lymphoma |
| title_short | PD-L1 is upregulated by EBV-driven LMP1 through NF-κB pathway and correlates with poor prognosis in natural killer/T-cell lymphoma |
| title_sort | pd l1 is upregulated by ebv driven lmp1 through nf κb pathway and correlates with poor prognosis in natural killer t cell lymphoma |
| topic | Natural killer/T-cell lymphoma Latent membrane protein 1 Epstein–Barr virus Programmed cell death receptor 1 |
| url | http://link.springer.com/article/10.1186/s13045-016-0341-7 |
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