Abstract

MicroRNAs (miRNAs) are involved in lymphoma progression by regulating the tumor microenvironment. Serum miR130b is overexpressed in diffuse large B-cell lymphoma (DLBCL), inducing Th17 cell alterations. To further illustrate its biological significance and therapeutic rationale, miR130b was detected by quantitative real-time PCR in the serum samples of 532 newly diagnosed DLBCL patients. The mechanism of miR130b on lymphoma progression and the tumor microenvironment was investigated both in vitro and in vivo. Therapeutic targeting miR130b was also evaluated, including OX40 agonistic antibody and lipid nanoparticles (LNPs)-miR130b antagomir. The results showed that serum miR130b significantly correlated with tumor miR130b and serum interleukin-17, indicating lymphoma relapse and inferior survival of DLBCL patients. MiR130b overexpression altered tumor microenvironment signaling pathways and increased Th17 cell activity. As mechanism of action, miR130b downregulated tumor OX40L expression by directly targeting IFNAR1/p-STAT1 axis, recruiting Th17 cells via OX40/OX40L interaction, thereby promoting immunosuppressive function of Th17 cells. In co-culture systems of B-lymphoma cells with immune cells, miR130b inhibited lymphoma cell autophagy, which could be counteracted by OX40 agonistic antibody and LNPs-miR130b antagomir. In murine xenograft model established with subcutaneous injection of A20 cells, both OX40 agonistic antibody and LNPs-miR130b antagomir remarkably inhibited Th17 cells and retarded miR130b-overexpressing tumor growth. In conclusion, as an oncogenic biomarker of DLBCL, miR130b was related to lymphoma progression through modulating OX40/OX40L-mediated lymphoma cell interaction with Th17 cells, attributing to B-cell lymphoma sensitivity towards OX40 agonistic antibody. Targeting miR130b using LNPs-miR130b antagomir could also be a potential immunotherapeutic strategy in treating OX40-altered lymphoid malignancies.

Details

Title
Therapeutic targeting miR130b counteracts diffuse large B-cell lymphoma progression via OX40/OX40L-mediated interaction with Th17 cells
Author
Sun, Rui 1 ; Pei-Pei, Zhang 2 ; Xiang-Qin, Weng 1 ; Xiao-Dong, Gao 1 ; Chuan-Xin, Huang 3   VIAFID ORCID Logo  ; Wang, Li 1 ; Xiao-Xia, Hu 1 ; Peng-Peng, Xu 1 ; Cheng, Lin 1 ; Lu, Jiang 1 ; Fu, Di 1 ; Qu Bin 4 ; Zhao, Yan 1 ; Feng, Yan 5 ; Hong-Jing, Dou 2 ; Zheng, Zhong 1 ; Wei-Li, Zhao 1 

1  Ruijin Hospital, Shanghai Jiao Tong University of Medicine, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Shanghai, China (GRID:grid.412277.5) (ISNI:0000 0004 1760 6738) 
2  Shanghai Jiao Tong University, State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, National Research Center for Translational Medicine at Shanghai, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293) 
3  Shanghai Jiao Tong University School of Medicine, Department of Immunobiology and Microbiology, Shanghai Institute of Immunology, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293) 
4  Shanghai Jiao Tong University School of Medicine, Department of Laboratory Medicine, Shanghai RuiJin Hospital, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293) 
5  Shanghai Jiao Tong University, State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
ISSN
20959907
e-ISSN
20593635
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41392-022-00895-2
ProQuest document ID
2640574003
Copyright
© The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.