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

• DOI: 10.1016/j.bbrc.2023.01.005
• Publication Date: 2023-01-06T07:17:39Z
• Authors: 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
• Keywords: HOTAIR; Regulatory B cells; Exosome

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.