Dap10 co-stimulation enhances the anti-HCC efficacy of NKp30 chimeric antigen receptor T cells
Chimeric antigen receptor (CAR) T-cell immunotherapy has made significant breakthroughs in the treatment of relapsed or refractory hematologic malignancies, but its efficacy in solid tumors remains limited. In this study, we developed a chimeric NKp30 (chNKp30) receptor whose ligand, B7H6, is often...
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| Format: | Article |
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Elsevier
2025-07-01
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| Series: | Translational Oncology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523325001561 |
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| author | JieYu Li LiMei Chen MingShui Chen Miao Lin Zineng Xie HuiLing Wu ZhiFeng Zhou WanSong Lin |
| author_facet | JieYu Li LiMei Chen MingShui Chen Miao Lin Zineng Xie HuiLing Wu ZhiFeng Zhou WanSong Lin |
| author_sort | JieYu Li |
| collection | DOAJ |
| description | Chimeric antigen receptor (CAR) T-cell immunotherapy has made significant breakthroughs in the treatment of relapsed or refractory hematologic malignancies, but its efficacy in solid tumors remains limited. In this study, we developed a chimeric NKp30 (chNKp30) receptor whose ligand, B7H6, is often up-regulated in various tumor cells and sparsely expressed in healthy cells. Introduction of the cytoplasmic structural domain of dnax-activating protein 10 (DAP10) into CAR resulted in chNKp30-Dap10 CAR-T cells that showed superior cell proliferation, activation, and apoptosis inhibition after antigenic stimulation compared with conventional chNKp30-CD28 and chNKp30-Wt CAR-T cells lacking any structural domains, along with inducing a central memory T cell phenotype, whereas chNKp30-CD28 and chNKp30-Wt triggered an effector memory phenotype. In addition, chNKp30-Dap10 T cells secreted higher levels of pro-inflammatory cytokines such as IL-2, IFN-γ, and TNF-α, while chNKp30-CD28 T cells secreted more of the anti-inflammatory cytokine IL-10. In the killing assay, chNKp30-Dap10 T cells demonstrated stronger anti-tumor effects. Similarly, better tumor regression was observed in the hepatocellular carcinoma transplantation tumor model. These findings suggest that B7H6 is an attractive therapeutic target and DAP10 signaling is involved in the functional regulation of CAR-T cells in hepatocellular carcinoma, which may induce preferential cytokine profiling and differentiation for cancer therapy, and that NKp30-Dap10 CAR-T cell therapy offers a potential option for the treatment of hepatocellular carcinoma. |
| format | Article |
| id | doaj-art-b99bc57583ba457b97fee79f87cce23a |
| institution | Kabale University |
| issn | 1936-5233 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj-art-b99bc57583ba457b97fee79f87cce23a2025-08-20T03:53:52ZengElsevierTranslational Oncology1936-52332025-07-015710242510.1016/j.tranon.2025.102425Dap10 co-stimulation enhances the anti-HCC efficacy of NKp30 chimeric antigen receptor T cellsJieYu Li0LiMei Chen1MingShui Chen2Miao Lin3Zineng Xie4HuiLing Wu5ZhiFeng Zhou6WanSong Lin7Laboratory of Immuno-Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, PR China; Fuzhou University College of Chemistry, Fuzhou 350002, PR China; The School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, PR China; Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou 350014, Fujian Province, PR ChinaDepartment of Clinical Laboratory, Fuzhou 350014, PR ChinaLaboratory of Immuno-Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, PR China; Fuzhou University College of Chemistry, Fuzhou 350002, PR China; The School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, PR ChinaFuzhou University College of Chemistry, Fuzhou 350002, PR ChinaFuzhou University College of Chemistry, Fuzhou 350002, PR ChinaThe School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, PR ChinaLaboratory of Immuno-Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, PR China; Fuzhou University College of Chemistry, Fuzhou 350002, PR China; The School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, PR China; Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou 350014, Fujian Province, PR China; Corresponding authors at: Laboratory of Immuno-Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, No. 420 Fuma Road, Fuzhou City, Fujian Province, 350014, PR China.Laboratory of Immuno-Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, PR China; Fuzhou University College of Chemistry, Fuzhou 350002, PR China; The School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, PR China; Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou 350014, Fujian Province, PR China; Corresponding authors at: Laboratory of Immuno-Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, No. 420 Fuma Road, Fuzhou City, Fujian Province, 350014, PR China.Chimeric antigen receptor (CAR) T-cell immunotherapy has made significant breakthroughs in the treatment of relapsed or refractory hematologic malignancies, but its efficacy in solid tumors remains limited. In this study, we developed a chimeric NKp30 (chNKp30) receptor whose ligand, B7H6, is often up-regulated in various tumor cells and sparsely expressed in healthy cells. Introduction of the cytoplasmic structural domain of dnax-activating protein 10 (DAP10) into CAR resulted in chNKp30-Dap10 CAR-T cells that showed superior cell proliferation, activation, and apoptosis inhibition after antigenic stimulation compared with conventional chNKp30-CD28 and chNKp30-Wt CAR-T cells lacking any structural domains, along with inducing a central memory T cell phenotype, whereas chNKp30-CD28 and chNKp30-Wt triggered an effector memory phenotype. In addition, chNKp30-Dap10 T cells secreted higher levels of pro-inflammatory cytokines such as IL-2, IFN-γ, and TNF-α, while chNKp30-CD28 T cells secreted more of the anti-inflammatory cytokine IL-10. In the killing assay, chNKp30-Dap10 T cells demonstrated stronger anti-tumor effects. Similarly, better tumor regression was observed in the hepatocellular carcinoma transplantation tumor model. These findings suggest that B7H6 is an attractive therapeutic target and DAP10 signaling is involved in the functional regulation of CAR-T cells in hepatocellular carcinoma, which may induce preferential cytokine profiling and differentiation for cancer therapy, and that NKp30-Dap10 CAR-T cell therapy offers a potential option for the treatment of hepatocellular carcinoma.http://www.sciencedirect.com/science/article/pii/S1936523325001561DAP 10 signaling domainChimeric antigen receptor (CAR)NKP30Hepatocellular carcinoma |
| spellingShingle | JieYu Li LiMei Chen MingShui Chen Miao Lin Zineng Xie HuiLing Wu ZhiFeng Zhou WanSong Lin Dap10 co-stimulation enhances the anti-HCC efficacy of NKp30 chimeric antigen receptor T cells Translational Oncology DAP 10 signaling domain Chimeric antigen receptor (CAR) NKP30 Hepatocellular carcinoma |
| title | Dap10 co-stimulation enhances the anti-HCC efficacy of NKp30 chimeric antigen receptor T cells |
| title_full | Dap10 co-stimulation enhances the anti-HCC efficacy of NKp30 chimeric antigen receptor T cells |
| title_fullStr | Dap10 co-stimulation enhances the anti-HCC efficacy of NKp30 chimeric antigen receptor T cells |
| title_full_unstemmed | Dap10 co-stimulation enhances the anti-HCC efficacy of NKp30 chimeric antigen receptor T cells |
| title_short | Dap10 co-stimulation enhances the anti-HCC efficacy of NKp30 chimeric antigen receptor T cells |
| title_sort | dap10 co stimulation enhances the anti hcc efficacy of nkp30 chimeric antigen receptor t cells |
| topic | DAP 10 signaling domain Chimeric antigen receptor (CAR) NKP30 Hepatocellular carcinoma |
| url | http://www.sciencedirect.com/science/article/pii/S1936523325001561 |
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