Journal Article

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

Baheti, Tasiken, Pu, Liyong, Zhang, Liren, Wang, Xuehao, Li, Qing, Qian, Xiaofeng, Zhang, Yu, Xia, Yongxiang, Hua, Dongxu, Zhang, Chuanyong, Xu, Jiali, Zhang, Ruizhi, Xu, Jing, You, Wenhua, Yao, Feifan, Dai, Yongjiu, Zhou, Suiqing, Huang, Wei, Tang, Jinhai, Dai, Jingjing

2022

Overview

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. Members of the PRDI-BF1 and RIZ homology domain (PRDM) family have been involved in the regulation of several pathological conditions, including cancer. Here the authors show that PRDM1/BLIMP1 promotes immune evasion by regulating PD-L1 expression in hepatocellular carcinoma cells.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/31 / 13/51 / 14/19 / 38/15 / 38/88 / 49/109 / 49/47 / 631/67/1059 / 631/67/2329 / 64/60 / 82/1 / 82/81 / Animal models / Animals / Anticancer properties / Antigens / Apoptosis / B7-H1 Antigen / Biodegradation / Cancer / Carcinoma, Hepatocellular / CD8 antigen / CD8-Positive T-Lymphocytes / Cell death / Effectiveness / Hepatocellular carcinoma / Homology / Humanities and Social Sciences / Immune Evasion / Liver cancer / Liver Neoplasms / Lymphocytes / Lymphocytes T / Mice / multidisciplinary / PD-1 protein / PD-L1 protein / Positive Regulatory Domain I-Binding Factor 1 - genetics / Positive Regulatory Domain I-Binding Factor 1 - metabolism / Programmed Cell Death 1 Receptor / Receptors / Science / Science (multidisciplinary)