Exosomal lncRNA HOTAIR induces PDL1+ B cells to impede anti-tumor immunity in colorectal cancer

Zhangjuan Xie; Jie Xia; Mengxia Jiao; Pengyuan Zhao; Zhiqiang Wang; Shengli Lin; Yun Xing; Yifan Li; Zhou Lu; Ziwen Zhong; Changhong Miao; Pinghong Zhou; Jiawen Qian; Luman Wang; Dan Zhang; Jie Gu; Yiwei Chu; Ronghua Liu

doi:10.1016/j.bbrc.2023.01.005

Exosomal lncRNA HOTAIR induces PDL1⁺ B cells to impede anti-tumor immunity in colorectal cancer

Biochem Biophys Res Commun. 2023 Feb 12:644:112-121. doi: 10.1016/j.bbrc.2023.01.005. Epub 2023 Jan 6.

Authors

Zhangjuan Xie¹, Jie Xia¹, Mengxia Jiao¹, Pengyuan Zhao¹, Zhiqiang Wang², Shengli Lin³, Yun Xing¹, Yifan Li⁴, Zhou Lu⁵, Ziwen Zhong⁵, Changhong Miao⁵, Pinghong Zhou³, Jiawen Qian⁶, Luman Wang⁴, Dan Zhang¹, Jie Gu³, Yiwei Chu⁷, Ronghua Liu⁸

Affiliations

¹ Shanghai Fifth People's Hospital, and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
² Shanghai Fifth People's Hospital, and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China; Department of Immunology, School of Basic Medical Sciences and Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
³ Endoscopy Center and Endoscopy Research Institute and Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
⁴ Department of Immunology, School of Basic Medical Sciences and Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
⁵ Liver Cancer Institute and Department of Anesthesiology, Department of Endocrinology, Zhongshan Hospital, Shanghai, 200032, China.
⁶ Department of Immunology, School of Basic Medical Sciences and Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China; Biotherapy Research Center, Fudan University, Shanghai, 200032, China.
⁷ Department of Immunology, School of Basic Medical Sciences and Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China; Liver Cancer Institute and Department of Anesthesiology, Department of Endocrinology, Zhongshan Hospital, Shanghai, 200032, China. Electronic address: yiweichu@fudan.edu.cn.
⁸ Shanghai Fifth People's Hospital, and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China. Electronic address: ronghualiu@fudan.edu.cn.

PMID: 36640665
DOI: 10.1016/j.bbrc.2023.01.005

Abstract

Regulatory B cells (Bregs) contribute to tumor immunosuppression. However, how B cells acquire their regulatory features in tumors remain unclear. Exosomes are important messengers that transmit tumor information to remodel tumor immunity. Here we revealed that tumor-derived exosomes drive Bregs to suppress anti-tumor immunity by delivering long non-coding RNAs (lncRNAs). HOTAIR was screened by lncRNA profiling in both colorectal cancer (CRC)-derived exosomes and infiltrating B cells. Tumor-derived HOTAIR polarized B cells toward a regulatory feature marked by programmed cell death-ligand 1 (PDL1) in CRC, and induced PDL1⁺ B cells to suppress CD8⁺ T cell activity. Exosomal HOTAIR bound to and protected pyruvate kinase M2 (PKM2) against ubiquitination degradation, resulting in STAT3 activation and PDL1 expression. Results from CRC patients showed a positive correlation between exosomal HOTAIR and tumor-infiltrating PDL1⁺ B cells. These findings reveal how B cells acquire PDL1-dominant regulatory feature in CRC, implying the clinical significance of exosomal therapy targeting HOTAIR.

Keywords: CRC; Exosome; HOTAIR; PDL1; Regulatory B cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Colorectal Neoplasms* / pathology
Exosomes* / metabolism
Humans
Lymphoma, B-Cell / immunology
RNA, Long Noncoding* / genetics
RNA, Long Noncoding* / metabolism

Substances

RNA, Long Noncoding