MZF1 promotes tumour progression and resistance to anti-PD-L1 antibody treatment in hepatocellular carcinoma
Background & Aims: The mechanism underlying resistance to immunotherapy involves engagement of immune checkpoint pathways. The transcriptional and epigenetic processes of checkpoint molecules, however, have not been well investigated. We thus studied whether the transcription factor myeloid...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-01-01
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| Series: | JHEP Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589555923002707 |
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| author | Anna Kan Shuang Liu Minke He Dongsheng Wen Haijing Deng Lichang Huang Zhicheng Lai Yexing Huang Ming Shi |
| author_facet | Anna Kan Shuang Liu Minke He Dongsheng Wen Haijing Deng Lichang Huang Zhicheng Lai Yexing Huang Ming Shi |
| author_sort | Anna Kan |
| collection | DOAJ |
| description | Background & Aims: The mechanism underlying resistance to immunotherapy involves engagement of immune checkpoint pathways. The transcriptional and epigenetic processes of checkpoint molecules, however, have not been well investigated. We thus studied whether the transcription factor myeloid zinc finger 1 (MZF1) may promote resistance to immunotherapy in hepatocellular carcinoma (HCC). Methods: Single-cell RNA-sequencing was performed to study the correlation between MZF1 and tumour microenvironment features in six patients with HCC. Combined immunohistochemistry and multi-immunofluorescence analyses were performed for verification. Ectopic expression of MZF1 was used in both orthotopic and genetically engineered hydrodynamic mouse HCC models for in vivo experiments. Proteome analysis, including protein degradation assays, ubiquitination assays, and co-immunoprecipitation assays, revealed the function of MZF1 in immune checkpoint pathways. Results: Single-cell RNA-sequencing suggested an immunosuppressive environment and a strong correlation with the immune checkpoint programmed death ligand 1 (PD-L1) in MZF1-overexpressing tumours. Analyses of 163 HCC samples demonstrated that MZF1 expression in HCC cells is associated with decreased T-cell infiltration. In vivo experiments showed that ectopic MZF1 expression in HCC cells impairs T-cell recruitment, resulting in resistance to immune checkpoint blockade. Mechanistically, MZF1 accelerated PD-L1 ubiquitination by binding to the cyclin-dependent kinase 4 (CDK4) activation site, while a direct bond between CDK4 and MZF1 led to increased MZF1 expression. Conclusions: MZF1 promotes PD-L1 ubiquitination via CDK4 and possibly MZF1. Inhibition of CDK4 can therefore restore PD-L1 expression and may be a potential strategy for combination with anti-PD-L1 antibodies. Impact and implications: Resistance to immune checkpoint blockade with anti-programmed death ligand 1 (PD-L1) antibody therapy is attributed to oncogenic alterations of tumour cells, however, effective countermeasures are yet to be established. Here, we report that the transcription factor myeloid zinc finger 1 (MZF1) can bind to the cyclin-dependent kinase 4 (CDK4) activation site and accelerate PD-L1 ubiquitination. A CDK4 inhibitor therefore enhances anti-PD-L1 antibody efficacy by blocking MZF1 signalling. This indicates a potential benefit of combining CDK4 inhibitors and anti-PD-L1 antibodies for the treatment of advanced HCC. |
| first_indexed | 2024-03-08T12:52:46Z |
| format | Article |
| id | doaj.art-cda62f388495470fb94d6ce8c3575d80 |
| institution | Directory Open Access Journal |
| issn | 2589-5559 |
| language | English |
| last_indexed | 2024-03-08T12:52:46Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | JHEP Reports |
| spelling | doaj.art-cda62f388495470fb94d6ce8c3575d802024-01-20T04:46:19ZengElsevierJHEP Reports2589-55592024-01-0161100939MZF1 promotes tumour progression and resistance to anti-PD-L1 antibody treatment in hepatocellular carcinomaAnna Kan0Shuang Liu1Minke He2Dongsheng Wen3Haijing Deng4Lichang Huang5Zhicheng Lai6Yexing Huang7Ming Shi8Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center; Guangzhou, China; State Key Laboratory of Oncology in South China; Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center; Guangzhou, China; Corresponding authors. Address: Department of Hepatic Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road, Guangzhou 510060, Guangdong, People’s Republic of China.Department of Oncology, The Third Affiliated Hospital of Soochow University; Changzhou, ChinaDepartment of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center; Guangzhou, China; State Key Laboratory of Oncology in South China; Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center; Guangzhou, ChinaDepartment of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center; Guangzhou, China; State Key Laboratory of Oncology in South China; Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center; Guangzhou, ChinaDepartment of Pathology, University of Hong Kong, Hong Kong, ChinaDepartment of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center; Guangzhou, China; State Key Laboratory of Oncology in South China; Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center; Guangzhou, ChinaDepartment of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center; Guangzhou, China; State Key Laboratory of Oncology in South China; Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center; Guangzhou, ChinaDepartment of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center; Guangzhou, China; State Key Laboratory of Oncology in South China; Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center; Guangzhou, ChinaDepartment of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center; Guangzhou, China; State Key Laboratory of Oncology in South China; Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center; Guangzhou, China; Corresponding authors. Address: Department of Hepatic Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road, Guangzhou 510060, Guangdong, People’s Republic of China.Background & Aims: The mechanism underlying resistance to immunotherapy involves engagement of immune checkpoint pathways. The transcriptional and epigenetic processes of checkpoint molecules, however, have not been well investigated. We thus studied whether the transcription factor myeloid zinc finger 1 (MZF1) may promote resistance to immunotherapy in hepatocellular carcinoma (HCC). Methods: Single-cell RNA-sequencing was performed to study the correlation between MZF1 and tumour microenvironment features in six patients with HCC. Combined immunohistochemistry and multi-immunofluorescence analyses were performed for verification. Ectopic expression of MZF1 was used in both orthotopic and genetically engineered hydrodynamic mouse HCC models for in vivo experiments. Proteome analysis, including protein degradation assays, ubiquitination assays, and co-immunoprecipitation assays, revealed the function of MZF1 in immune checkpoint pathways. Results: Single-cell RNA-sequencing suggested an immunosuppressive environment and a strong correlation with the immune checkpoint programmed death ligand 1 (PD-L1) in MZF1-overexpressing tumours. Analyses of 163 HCC samples demonstrated that MZF1 expression in HCC cells is associated with decreased T-cell infiltration. In vivo experiments showed that ectopic MZF1 expression in HCC cells impairs T-cell recruitment, resulting in resistance to immune checkpoint blockade. Mechanistically, MZF1 accelerated PD-L1 ubiquitination by binding to the cyclin-dependent kinase 4 (CDK4) activation site, while a direct bond between CDK4 and MZF1 led to increased MZF1 expression. Conclusions: MZF1 promotes PD-L1 ubiquitination via CDK4 and possibly MZF1. Inhibition of CDK4 can therefore restore PD-L1 expression and may be a potential strategy for combination with anti-PD-L1 antibodies. Impact and implications: Resistance to immune checkpoint blockade with anti-programmed death ligand 1 (PD-L1) antibody therapy is attributed to oncogenic alterations of tumour cells, however, effective countermeasures are yet to be established. Here, we report that the transcription factor myeloid zinc finger 1 (MZF1) can bind to the cyclin-dependent kinase 4 (CDK4) activation site and accelerate PD-L1 ubiquitination. A CDK4 inhibitor therefore enhances anti-PD-L1 antibody efficacy by blocking MZF1 signalling. This indicates a potential benefit of combining CDK4 inhibitors and anti-PD-L1 antibodies for the treatment of advanced HCC.http://www.sciencedirect.com/science/article/pii/S2589555923002707tumour microenvironmentimmune checkpointtargeted therapy |
| spellingShingle | Anna Kan Shuang Liu Minke He Dongsheng Wen Haijing Deng Lichang Huang Zhicheng Lai Yexing Huang Ming Shi MZF1 promotes tumour progression and resistance to anti-PD-L1 antibody treatment in hepatocellular carcinoma JHEP Reports tumour microenvironment immune checkpoint targeted therapy |
| title | MZF1 promotes tumour progression and resistance to anti-PD-L1 antibody treatment in hepatocellular carcinoma |
| title_full | MZF1 promotes tumour progression and resistance to anti-PD-L1 antibody treatment in hepatocellular carcinoma |
| title_fullStr | MZF1 promotes tumour progression and resistance to anti-PD-L1 antibody treatment in hepatocellular carcinoma |
| title_full_unstemmed | MZF1 promotes tumour progression and resistance to anti-PD-L1 antibody treatment in hepatocellular carcinoma |
| title_short | MZF1 promotes tumour progression and resistance to anti-PD-L1 antibody treatment in hepatocellular carcinoma |
| title_sort | mzf1 promotes tumour progression and resistance to anti pd l1 antibody treatment in hepatocellular carcinoma |
| topic | tumour microenvironment immune checkpoint targeted therapy |
| url | http://www.sciencedirect.com/science/article/pii/S2589555923002707 |
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