Long noncoding RNA HITT coordinates with RGS2 to inhibit PD-L1 translation in T cell immunity

作者：Lin, Qingyu; Liu, Tong; Wang, Xingwen; Hou, Guixue; Xiang, Zhiyuan; Zhang, Wenxin; Zheng, Shanliang; Zhao, Dong; Leng, Qibin; Zhang, Xiaoshi; Lu, Minqiao; Guan, Tianqi; Liu, Hao; Hu, Ying^*

来源：Journal of Clinical Investigation, 2023, 133(11): e162951.

DOI：10.1172/JCI162951

• CANCER
• PROTEIN
• STABILIZATION
• REGULATOR

Programmed cell death ligand 1 (PD-L1) is an immune checkpoint protein frequently expressed in human cancers that contributes to immune evasion through its binding to PD-1 on activated T cells. Unveiling the mechanisms underlying PD-L1 expression is essential for understanding the impact of the immunosuppressive microenvironment and is also crucial for the purpose of reboosting antitumor immunity. However, how PD-L1 is regulated, particularly at translational levels, remains largely unknown. Here, we discovered that a long noncoding RNA (lncRNA), HIF-1 & alpha; inhibitor at translation level (HITT), was transactivated by E2F transcription factor 1 (E2F1) under IFN-& gamma; stimulation. It coordinated with regulator of G protein signaling 2 (RGS2) in binding to the 5 & PRIME; UTR of PD-L1, resulting in reduced PD-L1 translation. HITT expression enhanced T cell-mediated cytotoxicity both in vitro and in vivo in a PD-L1-dependent manner. The clinical correlation between HITT/PD-L1 and RGS2/PD-L1 expression was also detected in breast cancer tissues. Together, these findings demonstrate the role of HITT in antitumor T cell immunity, highlighting activation of HITT as a potential therapeutic strategy for enhancing cancer immunotherapy.

• 单位
  哈尔滨医科大学; 山东大学; y; 深圳华大基因研究院; 广州医学院