DENR controls JAK2 translation to induce PD-L1 expression for tumor immune evasion

Baiwen Chen, Jiajia Hu, Xianting Hu, Huifang Chen, Rujuan Bao, Yatao Zhou, Youqiong Ye, Meixiao Zhan (), Wei Cai (), Huabin Li () and Hua-Bing Li ()
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Baiwen Chen: Fudan University
Jiajia Hu: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Xianting Hu: Fudan University
Huifang Chen: Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine
Rujuan Bao: Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine
Yatao Zhou: Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine
Youqiong Ye: Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine
Meixiao Zhan: Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People’s Hospital, Zhuhai Hospital of Jinan University
Wei Cai: Shanghai Minimally Invasive Surgery Center, Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Huabin Li: Fudan University
Hua-Bing Li: Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract RNA-binding proteins (RBPs) can recognize thousands of RNAs that help to maintain cell homeostasis, and RBP dysfunction is frequently observed in various cancers. However, whether specific RBPs are involved in tumor immune evasion by regulating programmed death ligand-1 (PD-L1) is unclear. Here, we perform targeted RBP CRISPR/Cas9 screening and identify density regulated re-initiation and release factor (DENR) as a PD-L1 regulator. DENR-depleted cancer cells exhibit reduced PD-L1 expression in vitro and in vivo. DENR depletion significantly suppresses tumor growth and enhances the tumor-killing activity of CD8+ T cells. Mechanistically, DENR antagonizes the translational repression of three consecutive upstream open reading frames (uORFs) upstream of Janus kinase 2 (Jak2); thus, DENR deficiency impairs JAK2 translation and the IFNγ-JAK-STAT signaling pathway, resulting in reduced PD-L1 expression in tumors. Overall, we discover an RBP DENR that could regulate PD-L1 expression for tumor immune evasion, and highlight the potential of DENR as a therapeutic target for immunotherapy.

Date: 2022
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DOI: 10.1038/s41467-022-29754-y

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