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

• Published in: Nature communications 2022-12, Vol.13 (1), p.7677-7677, Article 7677
• Main Authors: Li, Qing, Zhang, Liren, You, Wenhua, Xu, Jiali, Dai, Jingjing, Hua, Dongxu, Zhang, Ruizhi, Yao, Feifan, Zhou, Suiqing, Huang, Wei, Dai, Yongjiu, Zhang, Yu, Baheti, Tasiken, Qian, Xiaofeng, Pu, Liyong, Xu, Jing, Xia, Yongxiang, Zhang, Chuanyong, Tang, Jinhai, Wang, Xuehao
• Format: Article
• Language: English
• Subjects: 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)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-35469-x

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.