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 10

RGS2, HITT, and PD-L1 are associated with each other in vivo.

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RGS2, HITT, and PD-L1 are associated with each other in vivo. (A) Expres...
(A) Expression of HITT in human breast tumors (T) and their paired adjacent normal controls (N) (n = 38) determined by qRT-PCR. (B and C) Representative WB (B) and quantification of PD-L1 proteins (C) in 38 pairs of breast cancer tissues and their adjacent normal controls. (D and E) The correlation between the fold change of HITT (D) and PD-L1 protein (E) and stages. (F) Lineal correlation analysis of the fold changes of HITT expression versus those of PD-L1 protein expression (P = 0.021). (G) Quantification of RGS2 proteins in 38 pairs of breast cancer tissues and their adjacent normal controls. (H) Correlation between fold change of RGS2 protein and TNM stages. (I) Lineal correlation analysis of fold changes of RGS2 protein expression versus those of PD-L1 protein expression (P = 0.012). (J) Lineal correlation analysis of fold changes of HITT expression versus those of PD-L1 mRNA expression. (K) Lineal correlation analysis of fold changes of RGS2 protein expression versus those of PD-L1 mRNA expression. (L) Schematic diagram of RGS2/HITT/PD-L1–regulated interaction between cancer cells and T cells to modulate tumor immunity. IFN-γ secreted by activated T cells or others triggers E2F1-mediated transactivation of lncRNA HITT in cancer cells, where HITT directly binds with RGS2 and PD-L1–5′-UTR. This function of HITT also strengthens the direct interaction between RGS2 and PD-L1–5′-UTR. These interactions among HITT, RGS2, and PD-L1–5′-UTR lead to a retarded translation of PD-L1 and elevated T cell activation. Such activity of HITT is impaired in cancer cells due to the reduced expression of HITT. Activating HITT in cancer cells is a potential treatment for elevating T cell immunity. Data derived from 3 independent experiments are presented as mean ± SEM (A and C–K). **P < 0.01, Student’s t test (A, C–E, G, and H). Correlations were calculated according to Pearson’s correlation (F and I–K).