The molecular receptor NKBB enhances the persistence and anti-hepatocellular carcinoma activity of GPC3 CAR-T cells

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

doi:10.1016/j.phrs.2025.107619

The molecular receptor NKBB enhances the persistence and anti-hepatocellular carcinoma activity of GPC3 CAR-T cells

Pharmacol Res. 2025 Jan 20:107619. doi: 10.1016/j.phrs.2025.107619. Online ahead of print.

Authors

Minghao Sui¹, Tiantian Liu², Xuanli Song³, Ji Li⁴, Han Ding⁵, Yuqian Liu⁶, Xinyu Wang⁵, Huimin Liu⁷, Yuchan Xue⁵, Jianni Qi⁸, Miao Zhang⁹, Songbo Zhao¹⁰, Qiang Zhu¹¹

Affiliations

¹ Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China; Department of Infectious Disease, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China; Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
² Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China; Department of Infectious Disease, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
³ Institute for Bacterial Diseases, Jinan Center for Disease Control and Prevention, Jinan, 250021, Shandong, China.
⁴ Department of Spleen and stomach Hepatology, Digestive Center, the Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250001, Shandong, China.
⁵ Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
⁶ Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China.
⁷ Key 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, 250012, Shandong, China.
⁸ Department of Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
⁹ Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
¹⁰ Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China; Department of Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China. Electronic address: [email protected].
¹¹ Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China; Department of Infectious Disease, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China; Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China. Electronic address: [email protected].

PMID: 39842473
DOI: 10.1016/j.phrs.2025.107619

Abstract

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 (T_CM) 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.

Keywords: CAR-T; CTSL; GPC3; Hepatocellular carcinoma; IL-17; NKG2D.