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作者

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

作者单位

⁷Qilu Hospital of Shandong University, Jinan, Shandong 250012, China ³Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China ⁹Department of Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China ⁵Institute for Bacterial Diseases, Jinan Center for Disease Control and Prevention, Jinan, Shandong 250021, China ⁴These authors contributed equally to this work. ⁸Key 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, China ²Department of Infectious Disease, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China ⁶Department of Spleen and stomach Hepatology, Digestive Center, the Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250001, China ¹Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China ¹⁰Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China

刊名

Pharmacological Research

年份

2025

卷号

Vol.212

页码

107619

ISSN

1043-6618

关键词

CAR-T Hepatocellular carcinoma GPC3 NKG2D CTSL IL-17

摘要

Chimeric antigen receptor 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 , 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 CAR to construct GC3328z-NKBB CAR-T cells, which have double sp...更多

Chimeric antigen receptor 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 , 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 CAR to construct GC3328z-NKBB CAR-T cells, which have double specific targets of GPC3 and NKG2DLs , 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 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 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.收起

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