Long noncoding RNA HITT coordinates with RGS2 to inhibit PD-L1 translation in T cell immunity
Qingyu Lin, … , Hao Liu, Ying Hu
Qingyu Lin, … , Hao Liu, Ying Hu
Published April 4, 2023
Citation Information: J Clin Invest. 2023;133(11):e162951. https://doi.org/10.1172/JCI162951.
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Research Article Immunology Oncology

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

Abstract

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-1α inhibitor at translation level (HITT), was transactivated by E2F transcription factor 1 (E2F1) under IFN-γ stimulation. It coordinated with regulator of G protein signaling 2 (RGS2) in binding to the 5′ 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.

Authors

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

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Figure 5

RGS2 physically binds with PD-L1–5′-UTR.

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RGS2 physically binds with PD-L1–5′-UTR. (A) PD-L1–5′-UTR–driven lucifer...
(A) PD-L1–5′-UTR–driven luciferase activities determined in HITT stable lines with or without RGS2 KD. (B) PD-L1–5′-UTR levels determined by qRT-PCR following CLIP RGS2 in HITT-overexpressing stable HeLa cells, with GAPDH mRNA and CLIP IgG as negative controls. (C) GST-tagged RGS2 protein coprecipitated with biotin–PD-L1–5′-UTR or biotin-PD-L1–5′-UTR antisense control determined by WB. (D) Schematic of the compensatory mutations in PD-L1–5′-UTR (1–36 nt). GST-tagged RGS2 protein coprecipitated with biotin-PD-L1–5′-UTR (1–36 nt) or its mutants, determined by RNA pull-down assay. (E) PLA analysis of endogenous RGS2/exogenous PD-L1–5′-UTR or 5′-UTR (1-36 nt) MT4 in HeLa cells. (F) GST-tagged RGS2 or mutant proteins coprecipitated with biotin–PD-L1–5′-UTR (1–36 nt) determined by RNA pull-down assay. Data derived from 3 independent experiments are presented as mean ± SEM. **P < 0.01; ***P < 0.001; ****P < 0.0001; NS, not significant by Student’s t test (A) and 1-way ANOVA (B). Scale bars: 40 μm (left and center panels); 15 μm (right panels).