Radiotherapy enhances the anti-tumor effect of CAR-NK cells for hepatocellular carcinoma.
Carcinoma, Hepatocellular
/ radiotherapy
Killer Cells, Natural
/ immunology
Liver Neoplasms
/ radiotherapy
Animals
Humans
Cell Line, Tumor
Receptors, Chimeric Antigen
/ metabolism
Cell Movement
/ radiation effects
Glypicans
/ metabolism
Receptors, Interleukin-8B
/ metabolism
Xenograft Model Antitumor Assays
Mice
Gene Expression Regulation, Neoplastic
/ radiation effects
Immunotherapy, Adoptive
/ methods
Tumor Microenvironment
/ radiation effects
Cytotoxicity, Immunologic
/ radiation effects
Journal
Journal of translational medicine
ISSN: 1479-5876
Titre abrégé: J Transl Med
Pays: England
ID NLM: 101190741
Informations de publication
Date de publication:
13 Oct 2024
13 Oct 2024
Historique:
received:
17
05
2024
accepted:
01
10
2024
medline:
14
10
2024
pubmed:
14
10
2024
entrez:
13
10
2024
Statut:
epublish
Résumé
Chimeric antigen receptor (CAR)-NK cell therapy has shown remarkable clinical efficacy and safety in the treatment of hematological malignancies. However, this efficacy was limited in solid tumors owing to hostile tumor microenvironment (TME). Radiotherapy is commonly used for solid tumors and proved to improve the TME. Therefore, the combination with radiotherapy would be a potential strategy to improve therapeutic efficacy of CAR-NK cells for solid tumors. Glypican-3 (GPC3) was used as a target antigen of CAR-NK cell for hepatocellular carcinoma (HCC). To promote migration towards HCC, CXCR2-armed CAR-NK92 cells targeting GPC3 were first developed, and their cytotoxic and migration activities towards HCC cells were evaluated. Next, the effects of irradiation on the anti-tumor activity of CAR-NK92 cells were assessed in vitro and in HCC-bearing NCG mice. Lastly, to demonstrate the potential mechanism mediating the sensitized effect of irradiation on CAR-NK cells, the differential gene expression profiles induced by irradiation were analyzed and the expression of some important ligands for the NK-cell activating receptors were further determined by qRT-PCR and flow cytometry. In this study, we developed CXCR2-armed GPC3-targeting CAR-NK92 cells that exhibited specific and potent killing activity against HCC cells and the enhanced migration towards HCC cells. Pretreating HCC cells with irradiation enhanced in vitro anti-HCC effect and migration activity of CXCR2-armed CAR-NK92 cells. We further found that only high-dose (8 Gy) but not low-dose (2 Gy) irradiation in one fraction could significantly enhanced in vivo anti-HCC activity of CXCR2-armed CAR-NK92 cells. Irradiation with 8 Gy significantly up-regulated the expression of NK cell-activating ligands on HCC cells. Our results indicate the evidence that irradiation could efficiently enhance the anti-tumor effect of CAR-NK cells in solid tumor model. The combination with radiotherapy would be an attractive strategy to improve therapeutic efficacy of CAR-NK cells for solid tumors.
Sections du résumé
BACKGROUND
BACKGROUND
Chimeric antigen receptor (CAR)-NK cell therapy has shown remarkable clinical efficacy and safety in the treatment of hematological malignancies. However, this efficacy was limited in solid tumors owing to hostile tumor microenvironment (TME). Radiotherapy is commonly used for solid tumors and proved to improve the TME. Therefore, the combination with radiotherapy would be a potential strategy to improve therapeutic efficacy of CAR-NK cells for solid tumors.
METHODS
METHODS
Glypican-3 (GPC3) was used as a target antigen of CAR-NK cell for hepatocellular carcinoma (HCC). To promote migration towards HCC, CXCR2-armed CAR-NK92 cells targeting GPC3 were first developed, and their cytotoxic and migration activities towards HCC cells were evaluated. Next, the effects of irradiation on the anti-tumor activity of CAR-NK92 cells were assessed in vitro and in HCC-bearing NCG mice. Lastly, to demonstrate the potential mechanism mediating the sensitized effect of irradiation on CAR-NK cells, the differential gene expression profiles induced by irradiation were analyzed and the expression of some important ligands for the NK-cell activating receptors were further determined by qRT-PCR and flow cytometry.
RESULTS
RESULTS
In this study, we developed CXCR2-armed GPC3-targeting CAR-NK92 cells that exhibited specific and potent killing activity against HCC cells and the enhanced migration towards HCC cells. Pretreating HCC cells with irradiation enhanced in vitro anti-HCC effect and migration activity of CXCR2-armed CAR-NK92 cells. We further found that only high-dose (8 Gy) but not low-dose (2 Gy) irradiation in one fraction could significantly enhanced in vivo anti-HCC activity of CXCR2-armed CAR-NK92 cells. Irradiation with 8 Gy significantly up-regulated the expression of NK cell-activating ligands on HCC cells.
CONCLUSIONS
CONCLUSIONS
Our results indicate the evidence that irradiation could efficiently enhance the anti-tumor effect of CAR-NK cells in solid tumor model. The combination with radiotherapy would be an attractive strategy to improve therapeutic efficacy of CAR-NK cells for solid tumors.
Identifiants
pubmed: 39396988
doi: 10.1186/s12967-024-05724-4
pii: 10.1186/s12967-024-05724-4
doi:
Substances chimiques
Receptors, Chimeric Antigen
0
Glypicans
0
Receptors, Interleukin-8B
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
929Subventions
Organisme : National Natural Science Foundation of China
ID : 82373302
Organisme : National Natural Science Foundation of China
ID : 82102890
Organisme : Guangzhou Municipal Science and Technology Project
ID : 2024A04J6613
Organisme : Guangzhou Municipal Science and Technology Project
ID : 2023A04J2362
Organisme : Basic and Applied Basic Research Foundation of Guangdong Province
ID : 2023A1515030044
Informations de copyright
© 2024. The Author(s).
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