Exosomal lncRNA HOTAIR induces PDL1+ B cells to impede anti-tumor immunity in colorectal cancer
Exosomal lncRNA HOTAIR induces PDL1+ B cells to impede anti-tumor immunity in colorectal cancer
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外泌体 lncRNA HOTAIR 诱导 PDL1 B 细胞阻碍结直肠癌的抗肿瘤免疫
DOI：
10.1016/j.bbrc.2023.01.005
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发表时间：
2023
影响因子：
3.1
通讯作者：
Ronghua Liu
中科院分区：
文献类型：
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作者：
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
调节性B细胞（BCRs）有助于肿瘤免疫抑制。然而，B细胞如何在肿瘤中获得其调节特征仍不清楚。外泌体是传递肿瘤信息以重塑肿瘤免疫的重要信使。在这里，我们揭示了肿瘤来源的外泌体通过递送长的非编码RNA（lncRNA）来驱动BcRNA抑制抗肿瘤免疫。通过在结肠直肠癌（CRC）衍生的外来体和浸润性B细胞中的lncRNA谱分析来筛选HOTAIR。肿瘤来源的HOTAIR使B细胞向CRC中以程序性细胞死亡配体1（PDL 1）为标志的调节特征极化，并诱导PDL 1 +B细胞抑制CD 8 +T细胞活性。外泌体HOTAIR结合并保护丙酮酸激酶M2（PKM2）免受泛素化降解，导致STAT3活化和PDL 1表达。来自CRC患者的结果显示外泌体HOTAIR与肿瘤浸润的PDL 1 +B细胞之间呈正相关。这些发现揭示了B细胞如何在CRC中获得PDL 1主导的调节特征，暗示了靶向HOTAIR的外泌体治疗的临床意义。
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.