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Published on: January 3, 2013
PRDM1/BLIMP1 induces cancer immune evasion by modulating the USP22-SPI1-PD-L1 axis in hepatocellular carcinoma cells
Qing Li1, Liren Zhang1, Wenhua You2,3
1Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China.
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.
Insights
Overexpressing Prdm1 in hepatocellular carcinoma (HCC) increases PD-L1, dampening anti-tumor immunity. Combining Prdm1 with PD-1 blockade offers a novel therapeutic strategy for HCC treatment.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Programmed death receptor-1 (PD-1) blockade shows limited efficacy in hepatocellular carcinoma (HCC).
- The mechanisms regulating programmed cell death 1 ligand 1 (PD-L1) in HCC are not fully understood.
- PD-L1 binding to PD-1 on T cells suppresses anti-tumor immune responses.
Purpose of the Study:
- To investigate the role of Prdm1 in regulating PD-L1 expression and anti-tumor immunity in HCC.
- To elucidate the molecular mechanisms by which Prdm1 influences PD-L1 levels.
- To evaluate the therapeutic potential of combining Prdm1 overexpression with PD-1 blockade in HCC.
Main Methods:
- Utilized immune-deficient and immune-competent mouse models of HCC with tumoral Prdm1 overexpression.
- Investigated the effects of Prdm1 on PD-L1 expression, T cell exhaustion, and tumor growth.
- Performed mechanistic studies involving USP22, SPI1, and PD-L1 transcription and protein degradation.
- Assessed the efficacy of PD-1 monoclonal antibody (mAb) treatment in combination with Prdm1 overexpression.
Main Results:
- Tumoral Prdm1 overexpression inhibited tumor growth in immune-deficient models but dampened anti-tumor immunity in immune-competent models by upregulating PD-L1.
- Mechanistically, PRDM1 enhances USP22 transcription, leading to deubiquitination and reduced degradation of SPI1 protein, which in turn enhances PD-L1 transcription.
- PD-1 mAb treatment potentiated the anti-tumor effects of Prdm1 overexpression in HCC models.
- The PRDM1-USP22-SPI1 axis was identified as a key regulator of PD-L1 levels and CD8+ T cell exhaustion.
Conclusions:
- The PRDM1-USP22-SPI1 signaling pathway plays a critical role in regulating PD-L1 expression and immune evasion in HCC.
- Prdm1 overexpression contributes to T cell exhaustion by increasing PD-L1 levels.
- Combination therapy involving Prdm1 overexpression and PD-(L)1 blockade represents a promising therapeutic strategy for HCC.
