机构：[1]Department of Radiology, Translational Medicine Center, Guangzhou Key Laboratory for Research and Development of Nano-Biomedical Technology for Diagnosis and Therapy & Guangdong Provincial Education Department Key Laboratory of Nano-Immunoregulation Tumour Microenvironment, Central Laboratory, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China.[2]Department of Radiology, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang 441000, China.[3]Department of Nutrition, Guangdong Provincial Key Laboratory of Food, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.[4]Department of Radiology, Shunde Chinese Medicine Hospital, the Affiliated Hospital of Traditional Chinese Medicine University of Guangzhou, Foshan 528000, China.[5]Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, China.[6]Department of Pathology, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China.[7]Minimally Invasive Interventional Division, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.[8]Department of Interventional Therapy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510260, China.中山大学附属第二医院[9]Earle A. Chiles Research Institute, Providence Cancer Institute, 4805 NE Glisan St., Suite 2N35, Portland, OR 97213, USA.
Background: The application of chimeric antigen receptor (CAR) NK cells in solid tumors is hindered by lack of tumor -specific targets and inefficient CAR-NK cell efficacy. Claudin-6 (CLDN6) has been reported to be overexpressed in ovarian cancer and may be an attractive target for CAR-NK cells immunotherapy. However, the feasibility of using anti-CLDN6 CAR-NK cells to treat ovarian cancer remains to be explored. Methods: CLDN6 expression in primary human ovarian cancer, normal tissues and cell lines were detected by immunohistochemistry and western blot. Two types of third -generation CAR NK-92MI cells targeting CLDN6, CLDN6-CAR1 NK-92MI cells with domains containing self -activated elements (NKG2D, 2B4) and CLDN6-CAR2 NK-92MI cells with classical domains (CD28, 4-1BB) were constructed by lentivirus transfection, sorted by flow cytometry and verified by western blot and qPCR. OVCAR-3, SK-OV-3, A2780, Hey and PC -3 cells expressing the GFP and luciferase genes were transduced. Subcutaneous and intraperitoneal tumor models were established via NSG mice. The ability of CLDN6-CAR NK cells to kill CLDN6-positive ovarian cancer cells were evaluated in vitro and in vivo by live cell imaging and bioluminescence imaging. Results: Both CLDN6-CAR1 and CLDN6-CAR2 NK-92MI cells could specifically killed CLDN6-positive ovarian cancer cells (OVCAR-3, SK-OV-3, A2780 and Hey), rather than CLDN6 negative cell (PC -3), in vitro. CLDN6-CAR1 NK-92MI cells with domains containing self -activated elements (NKG2D, 2B4) exhibited stronger cytotoxicity than CLDN6-CAR2 NK-92MI cells with classical domains (CD28, 4-1BB). Furthermore, CLDN6-CAR1 NK cells could effectively eliminate ovarian cancer cells in subcutaneous and intraperitoneal tumor models. More importantly, CAR-NK cells combined with immune checkpoint inhibitors, anti -PD -L1, could synergistically enhance the antitumor efficacy of CLDN6-targeted CAR-NK cells. Conclusions: These results indicate that CLDN6-CAR NK cells possess strong antitumor activity and represent a promising immunotherapeutic modality for ovarian cancer.
基金：
This research was supported by the National
Natural Science Foundation of China (No. 82102860 to
S.Y.; No. 81872069 to Z. Z.; No. 81872613 and No.
81573142 to L. Y.) and Guangzhou Municipal Science
and Technology Project (No. 2023A04J0594 to D. C.)
第一作者机构：[1]Department of Radiology, Translational Medicine Center, Guangzhou Key Laboratory for Research and Development of Nano-Biomedical Technology for Diagnosis and Therapy & Guangdong Provincial Education Department Key Laboratory of Nano-Immunoregulation Tumour Microenvironment, Central Laboratory, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China.[2]Department of Radiology, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang 441000, China.
共同第一作者：
通讯作者：
通讯机构：[1]Department of Radiology, Translational Medicine Center, Guangzhou Key Laboratory for Research and Development of Nano-Biomedical Technology for Diagnosis and Therapy & Guangdong Provincial Education Department Key Laboratory of Nano-Immunoregulation Tumour Microenvironment, Central Laboratory, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China.[*1]the Second Affiliated Hospital of Guangzhou Medical University, 250 Changgangdong Road, Guangzhou 510260, China
推荐引用方式(GB/T 7714)：
Junping Li,Hong Hu,Hui Lian,et al.NK-92MI Cells Engineered with Anti-claudin-6 Chimeric Antigen Receptors in Immunotherapy for Ovarian Cancer[J].INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES.2024,20(5):1578-1601.doi:10.7150/ijbs.88539.
APA：
Junping Li,Hong Hu,Hui Lian,Shuo Yang,Manting Liu...&Zhenfeng Zhang.(2024).NK-92MI Cells Engineered with Anti-claudin-6 Chimeric Antigen Receptors in Immunotherapy for Ovarian Cancer.INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES,20,(5)
MLA：
Junping Li,et al."NK-92MI Cells Engineered with Anti-claudin-6 Chimeric Antigen Receptors in Immunotherapy for Ovarian Cancer".INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES 20..5(2024):1578-1601
生物学