The molecular receptor NKBB enhances the persistence and anti-hepatocellular carcinoma activity of GPC3 CAR-T cells
Chimeric antigen receptor (CAR) T cells have encouraging results in the treatment of hematological malignancies. However, CAR-T therapy still faces numerous challenges against solid tumors, such as hepatocellular carcinoma (HCC), owing to heterogeneous antigen expression in tumor cells, limited pers...
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Elsevier
2025-02-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661825000441 |
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| author | Minghao Sui Tiantian Liu Xuanli Song Ji Li Han Ding Yuqian Liu Xinyu Wang Huimin Liu Yuchan Xue Jianni Qi Miao Zhang Songbo Zhao Qiang Zhu |
| author_facet | Minghao Sui Tiantian Liu Xuanli Song Ji Li Han Ding Yuqian Liu Xinyu Wang Huimin Liu Yuchan Xue Jianni Qi Miao Zhang Songbo Zhao Qiang Zhu |
| author_sort | Minghao Sui |
| collection | DOAJ |
| description | Chimeric antigen receptor (CAR) T cells have encouraging results in the treatment of hematological malignancies. However, CAR-T therapy still faces numerous challenges against solid tumors, such as hepatocellular carcinoma (HCC), owing to heterogeneous antigen expression in tumor cells, limited persistence of CAR-T cells, etc. Therefore, to treat HCC more effectively, we connected the molecular receptor NKBB to a second-generation glypican-3 (GPC3) CAR to construct GC3328z-NKBB CAR-T cells, which have double specific targets of GPC3 and NKG2DLs (natural killer group 2, member D ligands), dual co-stimulation of CD28 and 41BB, and a single CD3ζ chain. Our study showed that the molecular receptor NKBB conferred GPC3 CAR-T cells with enhanced migration and infiltration abilities towards HCC, higher central memory T (TCM) cell proportion and proliferation capacity, and reduced exhaustion level. GC3328z-NKBB CAR-T cells exhibited improved cytotoxicity against HCC cells and prolonged persistence. The cathepsin L/interleukin-17 (CTSL/IL-17) axis contributed to the superior anti-HCC activity of GC3328z-NKBB CAR-T cells. Overall, the molecular receptor NKBB significantly increased the persistence of GPC3 CAR-T cells, and GC3328z-NKBB CAR-T cells possessed potent anti-HCC activity in mice, providing a new strategy for the potential improvement of adoptive T cell therapy in the treatment of HCC. |
| format | Article |
| id | doaj-art-b1b929dc43cc4de28d67375823281ca2 |
| institution | Kabale University |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-b1b929dc43cc4de28d67375823281ca22025-02-08T04:59:53ZengElsevierPharmacological Research1096-11862025-02-01212107619The molecular receptor NKBB enhances the persistence and anti-hepatocellular carcinoma activity of GPC3 CAR-T cellsMinghao Sui0Tiantian Liu1Xuanli Song2Ji Li3Han Ding4Yuqian Liu5Xinyu Wang6Huimin Liu7Yuchan Xue8Jianni Qi9Miao Zhang10Songbo Zhao11Qiang Zhu12Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China; Department of Infectious Disease, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, ChinaShandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China; Department of Infectious Disease, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, ChinaInstitute for Bacterial Diseases, Jinan Center for Disease Control and Prevention, Jinan, Shandong 250021, ChinaDepartment of Spleen and stomach Hepatology, Digestive Center, the Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250001, ChinaDepartment of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, ChinaQilu Hospital of Shandong University, Jinan, Shandong 250012, ChinaDepartment of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, ChinaKey Laboratory for Experimental Teratology of Ministry of Education, Shandong Key Laboratory of Infection and Immunity, and Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, ChinaDepartment of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, ChinaDepartment of Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, ChinaDepartment of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, ChinaShandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China; Department of Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Correspondence to: Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, 324 Jingwu Road, Jinan, Shandong 250021, China.Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China; Department of Infectious Disease, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Correspondence to: Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, 324 Jingwu Road, Jinan, Shandong 250021, China.Chimeric antigen receptor (CAR) T cells have encouraging results in the treatment of hematological malignancies. However, CAR-T therapy still faces numerous challenges against solid tumors, such as hepatocellular carcinoma (HCC), owing to heterogeneous antigen expression in tumor cells, limited persistence of CAR-T cells, etc. Therefore, to treat HCC more effectively, we connected the molecular receptor NKBB to a second-generation glypican-3 (GPC3) CAR to construct GC3328z-NKBB CAR-T cells, which have double specific targets of GPC3 and NKG2DLs (natural killer group 2, member D ligands), dual co-stimulation of CD28 and 41BB, and a single CD3ζ chain. Our study showed that the molecular receptor NKBB conferred GPC3 CAR-T cells with enhanced migration and infiltration abilities towards HCC, higher central memory T (TCM) cell proportion and proliferation capacity, and reduced exhaustion level. GC3328z-NKBB CAR-T cells exhibited improved cytotoxicity against HCC cells and prolonged persistence. The cathepsin L/interleukin-17 (CTSL/IL-17) axis contributed to the superior anti-HCC activity of GC3328z-NKBB CAR-T cells. Overall, the molecular receptor NKBB significantly increased the persistence of GPC3 CAR-T cells, and GC3328z-NKBB CAR-T cells possessed potent anti-HCC activity in mice, providing a new strategy for the potential improvement of adoptive T cell therapy in the treatment of HCC.http://www.sciencedirect.com/science/article/pii/S1043661825000441CAR-THepatocellular carcinomaGPC3NKG2DCTSLIL-17 |
| spellingShingle | Minghao Sui Tiantian Liu Xuanli Song Ji Li Han Ding Yuqian Liu Xinyu Wang Huimin Liu Yuchan Xue Jianni Qi Miao Zhang Songbo Zhao Qiang Zhu The molecular receptor NKBB enhances the persistence and anti-hepatocellular carcinoma activity of GPC3 CAR-T cells Pharmacological Research CAR-T Hepatocellular carcinoma GPC3 NKG2D CTSL IL-17 |
| title | The molecular receptor NKBB enhances the persistence and anti-hepatocellular carcinoma activity of GPC3 CAR-T cells |
| title_full | The molecular receptor NKBB enhances the persistence and anti-hepatocellular carcinoma activity of GPC3 CAR-T cells |
| title_fullStr | The molecular receptor NKBB enhances the persistence and anti-hepatocellular carcinoma activity of GPC3 CAR-T cells |
| title_full_unstemmed | The molecular receptor NKBB enhances the persistence and anti-hepatocellular carcinoma activity of GPC3 CAR-T cells |
| title_short | The molecular receptor NKBB enhances the persistence and anti-hepatocellular carcinoma activity of GPC3 CAR-T cells |
| title_sort | molecular receptor nkbb enhances the persistence and anti hepatocellular carcinoma activity of gpc3 car t cells |
| topic | CAR-T Hepatocellular carcinoma GPC3 NKG2D CTSL IL-17 |
| url | http://www.sciencedirect.com/science/article/pii/S1043661825000441 |
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