USP19 deficiency enhances T-cell-mediated antitumor immunity by promoting PD-L1 degradation in colorectal cancer
Colorectal cancer (CRC) is characterized by a highly immunosuppressive tumor microenvironment, which limits the effectiveness of current immunotherapies. Identifying strategies to overcome this resistance is critical for improving treatment outcomes. In this study, we discovered that USP19 plays a p...
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Elsevier
2025-04-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661825000933 |
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| author | Feng Shi Guang-Jing Li Yi Liu Hai-Meng Zhou Yue Zhang Si-Yi Wei Bo-Jun Zan Meng Gao Fei-Shan Chen Bo-Xin Li Bai-Qi Wang Ming-You Dong Run-Lei Du Xiao-Dong Zhang |
| author_facet | Feng Shi Guang-Jing Li Yi Liu Hai-Meng Zhou Yue Zhang Si-Yi Wei Bo-Jun Zan Meng Gao Fei-Shan Chen Bo-Xin Li Bai-Qi Wang Ming-You Dong Run-Lei Du Xiao-Dong Zhang |
| author_sort | Feng Shi |
| collection | DOAJ |
| description | Colorectal cancer (CRC) is characterized by a highly immunosuppressive tumor microenvironment, which limits the effectiveness of current immunotherapies. Identifying strategies to overcome this resistance is critical for improving treatment outcomes. In this study, we discovered that USP19 plays a pivotal role in regulating T-cell-mediated antitumor immunity through a CRISPR/Cas9 sgRNA library screen and co-culture assays with activated T cells. We demonstrated that USP19 deficiency significantly enhances the susceptibility to T cell-mediated cytotoxicity in CRC cells, organoids, and mouse models. Transcriptomic sequencing (RNA-seq) revealed activation of the PD-1 pathway in tumor with USP19-deficiency cells. Mechanistic investigations revealed that USP19 directly stabilizes PD-L1 by binding to its intracellular domain and preventing its degradation via K48-linked ubiquitination and proteasomal pathways. Clinically, USP19 expression was found to be significantly elevated in CRC tissues and was positively associated with PD-L1 levels, advanced tumor grade, poor differentiation, and TP53 mutations, highlighting its potential as a biomarker for aggressive CRC. Importantly, in vivo experiments demonstrated that targeting USP19, in combination with αPD-L1 therapy, synergistically suppressed CRC progression. This combination not only reduced PD-L1 levels but also enhanced CD8+ T-cell activation and GzmB infiltration, resulting in robust antitumor effects. These findings establish USP19 as a key driver of immune evasion in CRC and suggest that targeting USP19 could enhance the efficacy of immunotherapy, providing a promising new avenue for CRC treatment. |
| format | Article |
| id | doaj-art-c269e8933ed5426e84fe1c0fb77012f3 |
| institution | DOAJ |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-c269e8933ed5426e84fe1c0fb77012f32025-08-20T03:05:09ZengElsevierPharmacological Research1096-11862025-04-0121410766810.1016/j.phrs.2025.107668USP19 deficiency enhances T-cell-mediated antitumor immunity by promoting PD-L1 degradation in colorectal cancerFeng Shi0Guang-Jing Li1Yi Liu2Hai-Meng Zhou3Yue Zhang4Si-Yi Wei5Bo-Jun Zan6Meng Gao7Fei-Shan Chen8Bo-Xin Li9Bai-Qi Wang10Ming-You Dong11Run-Lei Du12Xiao-Dong Zhang13National Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, ChinaKey Laboratory of Research on Clinical Molecular Diagnosis for High Incidence Diseases in Western Guangxi of Guangxi Higher Education Institutions, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, ChinaNational Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, ChinaHubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, ChinaHubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, ChinaNational Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, ChinaMedical Laboratory College, Youjiang Medical University for Nationalities, Baise, Guangxi, ChinaNational Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, ChinaNational Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, ChinaNational Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, ChinaNational Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, ChinaNational Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, China; Corresponding authors.National Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, China; Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; Corresponding author at: National Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, China.National Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang 421001, China; Corresponding authors.Colorectal cancer (CRC) is characterized by a highly immunosuppressive tumor microenvironment, which limits the effectiveness of current immunotherapies. Identifying strategies to overcome this resistance is critical for improving treatment outcomes. In this study, we discovered that USP19 plays a pivotal role in regulating T-cell-mediated antitumor immunity through a CRISPR/Cas9 sgRNA library screen and co-culture assays with activated T cells. We demonstrated that USP19 deficiency significantly enhances the susceptibility to T cell-mediated cytotoxicity in CRC cells, organoids, and mouse models. Transcriptomic sequencing (RNA-seq) revealed activation of the PD-1 pathway in tumor with USP19-deficiency cells. Mechanistic investigations revealed that USP19 directly stabilizes PD-L1 by binding to its intracellular domain and preventing its degradation via K48-linked ubiquitination and proteasomal pathways. Clinically, USP19 expression was found to be significantly elevated in CRC tissues and was positively associated with PD-L1 levels, advanced tumor grade, poor differentiation, and TP53 mutations, highlighting its potential as a biomarker for aggressive CRC. Importantly, in vivo experiments demonstrated that targeting USP19, in combination with αPD-L1 therapy, synergistically suppressed CRC progression. This combination not only reduced PD-L1 levels but also enhanced CD8+ T-cell activation and GzmB infiltration, resulting in robust antitumor effects. These findings establish USP19 as a key driver of immune evasion in CRC and suggest that targeting USP19 could enhance the efficacy of immunotherapy, providing a promising new avenue for CRC treatment.http://www.sciencedirect.com/science/article/pii/S1043661825000933Colorectal cancerUbiquitin-specific protease 19Programmed death-ligand 1Tumor immunotherapy |
| spellingShingle | Feng Shi Guang-Jing Li Yi Liu Hai-Meng Zhou Yue Zhang Si-Yi Wei Bo-Jun Zan Meng Gao Fei-Shan Chen Bo-Xin Li Bai-Qi Wang Ming-You Dong Run-Lei Du Xiao-Dong Zhang USP19 deficiency enhances T-cell-mediated antitumor immunity by promoting PD-L1 degradation in colorectal cancer Pharmacological Research Colorectal cancer Ubiquitin-specific protease 19 Programmed death-ligand 1 Tumor immunotherapy |
| title | USP19 deficiency enhances T-cell-mediated antitumor immunity by promoting PD-L1 degradation in colorectal cancer |
| title_full | USP19 deficiency enhances T-cell-mediated antitumor immunity by promoting PD-L1 degradation in colorectal cancer |
| title_fullStr | USP19 deficiency enhances T-cell-mediated antitumor immunity by promoting PD-L1 degradation in colorectal cancer |
| title_full_unstemmed | USP19 deficiency enhances T-cell-mediated antitumor immunity by promoting PD-L1 degradation in colorectal cancer |
| title_short | USP19 deficiency enhances T-cell-mediated antitumor immunity by promoting PD-L1 degradation in colorectal cancer |
| title_sort | usp19 deficiency enhances t cell mediated antitumor immunity by promoting pd l1 degradation in colorectal cancer |
| topic | Colorectal cancer Ubiquitin-specific protease 19 Programmed death-ligand 1 Tumor immunotherapy |
| url | http://www.sciencedirect.com/science/article/pii/S1043661825000933 |
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