PRDM1/BLIMP1 induces cancer immune evasion by modulating the USP22-SPI1-PD-L1 axis in hepatocellular carcinoma cells

Qing Li, Liren Zhang, Wenhua You, Jiali Xu, Jingjing Dai, Dongxu Hua, Ruizhi Zhang, Feifan Yao, Suiqing Zhou, Wei Huang, Yongjiu Dai, Yu Zhang, Tasiken Baheti, Xiaofeng Qian, Liyong Pu, Jing Xu (), Yongxiang Xia (), Chuanyong Zhang (), Jinhai Tang () and Xuehao Wang ()
Additional contact information
Qing Li: NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University)
Liren Zhang: NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University)
Wenhua You: Southeast University
Jiali Xu: The First Affiliated Hospital of Nanjing Medical University
Jingjing Dai: The First Affiliated Hospital of Nanjing Medical University
Dongxu Hua: Nanjing Medical University
Ruizhi Zhang: NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University)
Feifan Yao: NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University)
Suiqing Zhou: NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University)
Wei Huang: Ili & Jiangsu Joint Institute of Health
Yongjiu Dai: NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University)
Yu Zhang: Ili & Jiangsu Joint Institute of Health
Tasiken Baheti: Ili & Jiangsu Joint Institute of Health
Xiaofeng Qian: NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University)
Liyong Pu: NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University)
Jing Xu: The First Affiliated Hospital of Nanjing Medical University
Yongxiang Xia: NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University)
Chuanyong Zhang: NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University)
Jinhai Tang: The First Affiliated Hospital of Nanjing Medical University
Xuehao Wang: NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University)

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Programmed death receptor-1 (PD-1) blockade have achieved some efficacy but only in a fraction of patients with hepatocellular carcinoma (HCC). Programmed cell death 1 ligand 1 (PD-L1) binds to its receptor PD1 on T cells to dampen antigen-tumor immune responses. However, the mechanisms underlying PD-L1 regulation are not fully elucidated. Herein, we identify that tumoral Prdm1 overexpression inhibits cell growth in immune-deficient mouse models. Further, tumoral Prdm1 overexpression upregulates PD-L1 levels, dampening anti-tumor immunity in vivo, and neutralizes the anti-tumor efficacy of Prdm1 overexpression in immune-competent mouse models. Mechanistically, PRDM1 enhances USP22 transcription, thus reducing SPI1 protein degradation through deubiquitination, which enhances PD-L1 transcription. Functionally, PD-1 mAb treatment reinforces the efficacy of Prdm1-overexpressing HCC immune-competent mouse models. Collectively, we demonstrate that the PRDM1-USP22-SPI1 axis regulates PD-L1 levels, resulting in infiltrated CD8+ T cell exhaustion. Furthermore, PRDM1 overexpression combined with PD-(L)1 mAb treatment provides a therapeutic strategy for HCC treatment.

Date: 2022
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DOI: 10.1038/s41467-022-35469-x

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