Cargando…

MiR155 sensitized B-lymphoma cells to anti-PD-L1 antibody via PD-1/PD-L1-mediated lymphoma cell interaction with CD8+T cells

BACKGROUND: MicroRNAs (miRs) are involved in lymphoma progression by regulating tumor cell interaction with microenvironment. MiR155 is overexpressed in diffuse large B-cell lymphoma (DLBCL) and its biological effect on tumor microenvironment needs to be futher investigated. METHODS: MiR155 was dete...

Descripción completa

Detalles Bibliográficos
Autores principales: Zheng, Zhong, Sun, Rui, Zhao, Hui-Jin, Fu, Di, Zhong, Hui-Juan, Weng, Xiang-Qin, Qu, Bin, Zhao, Yan, Wang, Li, Zhao, Wei-Li
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441197/
https://www.ncbi.nlm.nih.gov/pubmed/30925928
http://dx.doi.org/10.1186/s12943-019-0977-3
_version_ 1783407514007633920
author Zheng, Zhong
Sun, Rui
Zhao, Hui-Jin
Fu, Di
Zhong, Hui-Juan
Weng, Xiang-Qin
Qu, Bin
Zhao, Yan
Wang, Li
Zhao, Wei-Li
author_facet Zheng, Zhong
Sun, Rui
Zhao, Hui-Jin
Fu, Di
Zhong, Hui-Juan
Weng, Xiang-Qin
Qu, Bin
Zhao, Yan
Wang, Li
Zhao, Wei-Li
author_sort Zheng, Zhong
collection PubMed
description BACKGROUND: MicroRNAs (miRs) are involved in lymphoma progression by regulating tumor cell interaction with microenvironment. MiR155 is overexpressed in diffuse large B-cell lymphoma (DLBCL) and its biological effect on tumor microenvironment needs to be futher investigated. METHODS: MiR155 was detected by quantitative real-time PCR in patients with newly diagnosed DLBCL. The mechanism of action of miR155 on lymphoma progression and tumor microenvironment was examined in vitro in B-lymphoma cell lines and in vivo in a murine xenograft model. RESULTS: Serum miR155 was significantly elevated, correlated with tumor miR155 expression, and indicated poor disease outcome in DLBCL. MiR155 overexpression was associated with decreased peripheral blood CD8+T cells and inhibition of T-cell receptor signaling. Of note, EBV-positive patients showed higher serum miR155 than EBV-negative patients. In co-culture systems of B-lymphoma cells with immune cells, miR155 induced Fas-mediated apoptosis of CD8+T cells, which could be targeted by anti-PD-1 and anti-PD-L1 antibodies. Moreover, miR155 enhanced lymphoma cell PD-L1 expression, recruited CD8+T cells by PD-1/PD-L1 interaction and inhibited CD8+T cell function via dephosphorylating AKT and ERK. MiR155-induced AKT/ERK inactivation was more obvious in CD8+T cells co-cultured with EBV-infected B-lymphoma cells. In vivo in a murine xenograft model established with subcutaneous injection of A20 cells, PD-L1 blockade particularly retarded miR155-overexpressing tumor growth, consistent with maintenance of CD8+T cells and their function. CONCLUSIONS: As a oncogenic biomarker of B-cell lymphoma, serum miR155 was related to lymphoma progression through modulating PD-1/PD-L1-mediated interaction with CD8+T cells of tumor microenvironment, indicating the sensitivity of B-cell lymphoma to PD-L1 blockade. Also CD8+T cells could be a therapeutic mediator of immune checkpoint inhibitors in treating EBV-associated lymphoid malignancies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12943-019-0977-3) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-6441197
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-64411972019-04-11 MiR155 sensitized B-lymphoma cells to anti-PD-L1 antibody via PD-1/PD-L1-mediated lymphoma cell interaction with CD8+T cells Zheng, Zhong Sun, Rui Zhao, Hui-Jin Fu, Di Zhong, Hui-Juan Weng, Xiang-Qin Qu, Bin Zhao, Yan Wang, Li Zhao, Wei-Li Mol Cancer Research BACKGROUND: MicroRNAs (miRs) are involved in lymphoma progression by regulating tumor cell interaction with microenvironment. MiR155 is overexpressed in diffuse large B-cell lymphoma (DLBCL) and its biological effect on tumor microenvironment needs to be futher investigated. METHODS: MiR155 was detected by quantitative real-time PCR in patients with newly diagnosed DLBCL. The mechanism of action of miR155 on lymphoma progression and tumor microenvironment was examined in vitro in B-lymphoma cell lines and in vivo in a murine xenograft model. RESULTS: Serum miR155 was significantly elevated, correlated with tumor miR155 expression, and indicated poor disease outcome in DLBCL. MiR155 overexpression was associated with decreased peripheral blood CD8+T cells and inhibition of T-cell receptor signaling. Of note, EBV-positive patients showed higher serum miR155 than EBV-negative patients. In co-culture systems of B-lymphoma cells with immune cells, miR155 induced Fas-mediated apoptosis of CD8+T cells, which could be targeted by anti-PD-1 and anti-PD-L1 antibodies. Moreover, miR155 enhanced lymphoma cell PD-L1 expression, recruited CD8+T cells by PD-1/PD-L1 interaction and inhibited CD8+T cell function via dephosphorylating AKT and ERK. MiR155-induced AKT/ERK inactivation was more obvious in CD8+T cells co-cultured with EBV-infected B-lymphoma cells. In vivo in a murine xenograft model established with subcutaneous injection of A20 cells, PD-L1 blockade particularly retarded miR155-overexpressing tumor growth, consistent with maintenance of CD8+T cells and their function. CONCLUSIONS: As a oncogenic biomarker of B-cell lymphoma, serum miR155 was related to lymphoma progression through modulating PD-1/PD-L1-mediated interaction with CD8+T cells of tumor microenvironment, indicating the sensitivity of B-cell lymphoma to PD-L1 blockade. Also CD8+T cells could be a therapeutic mediator of immune checkpoint inhibitors in treating EBV-associated lymphoid malignancies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12943-019-0977-3) contains supplementary material, which is available to authorized users. BioMed Central 2019-03-30 /pmc/articles/PMC6441197/ /pubmed/30925928 http://dx.doi.org/10.1186/s12943-019-0977-3 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Zheng, Zhong
Sun, Rui
Zhao, Hui-Jin
Fu, Di
Zhong, Hui-Juan
Weng, Xiang-Qin
Qu, Bin
Zhao, Yan
Wang, Li
Zhao, Wei-Li
MiR155 sensitized B-lymphoma cells to anti-PD-L1 antibody via PD-1/PD-L1-mediated lymphoma cell interaction with CD8+T cells
title MiR155 sensitized B-lymphoma cells to anti-PD-L1 antibody via PD-1/PD-L1-mediated lymphoma cell interaction with CD8+T cells
title_full MiR155 sensitized B-lymphoma cells to anti-PD-L1 antibody via PD-1/PD-L1-mediated lymphoma cell interaction with CD8+T cells
title_fullStr MiR155 sensitized B-lymphoma cells to anti-PD-L1 antibody via PD-1/PD-L1-mediated lymphoma cell interaction with CD8+T cells
title_full_unstemmed MiR155 sensitized B-lymphoma cells to anti-PD-L1 antibody via PD-1/PD-L1-mediated lymphoma cell interaction with CD8+T cells
title_short MiR155 sensitized B-lymphoma cells to anti-PD-L1 antibody via PD-1/PD-L1-mediated lymphoma cell interaction with CD8+T cells
title_sort mir155 sensitized b-lymphoma cells to anti-pd-l1 antibody via pd-1/pd-l1-mediated lymphoma cell interaction with cd8+t cells
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441197/
https://www.ncbi.nlm.nih.gov/pubmed/30925928
http://dx.doi.org/10.1186/s12943-019-0977-3
work_keys_str_mv AT zhengzhong mir155sensitizedblymphomacellstoantipdl1antibodyviapd1pdl1mediatedlymphomacellinteractionwithcd8tcells
AT sunrui mir155sensitizedblymphomacellstoantipdl1antibodyviapd1pdl1mediatedlymphomacellinteractionwithcd8tcells
AT zhaohuijin mir155sensitizedblymphomacellstoantipdl1antibodyviapd1pdl1mediatedlymphomacellinteractionwithcd8tcells
AT fudi mir155sensitizedblymphomacellstoantipdl1antibodyviapd1pdl1mediatedlymphomacellinteractionwithcd8tcells
AT zhonghuijuan mir155sensitizedblymphomacellstoantipdl1antibodyviapd1pdl1mediatedlymphomacellinteractionwithcd8tcells
AT wengxiangqin mir155sensitizedblymphomacellstoantipdl1antibodyviapd1pdl1mediatedlymphomacellinteractionwithcd8tcells
AT qubin mir155sensitizedblymphomacellstoantipdl1antibodyviapd1pdl1mediatedlymphomacellinteractionwithcd8tcells
AT zhaoyan mir155sensitizedblymphomacellstoantipdl1antibodyviapd1pdl1mediatedlymphomacellinteractionwithcd8tcells
AT wangli mir155sensitizedblymphomacellstoantipdl1antibodyviapd1pdl1mediatedlymphomacellinteractionwithcd8tcells
AT zhaoweili mir155sensitizedblymphomacellstoantipdl1antibodyviapd1pdl1mediatedlymphomacellinteractionwithcd8tcells