Co-expression of IL-15 and CCL21 strengthens CAR-NK cells to eliminate tumors in concert with T cells and equips them with PI3K/AKT/mTOR signal signature
Background Chimeric antigen receptor (CAR)-natural killer (NK) cell therapy has demonstrated safety and feasibility in clinical settings; however, limited efficacy due to intrinsic dysfunction and extrinsic suppression remains an unresolved issue. T cells provide multifaceted support to NK cell-medi...
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BMJ Publishing Group
2025-06-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/6/e010822.full |
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| author | Jie Zhou Lu Tang Yu Hu Jun Deng Yingying Li Wei Xiong Jianghua Wu Jia Xu Wenjing Luo Heng Mei Xindi Wang Zhaozhao Chen Chenggong Li Zhongpei Huang Zhuolin Wu Yinqiang Zhang Yun Kang Qiaolin Liu |
| author_facet | Jie Zhou Lu Tang Yu Hu Jun Deng Yingying Li Wei Xiong Jianghua Wu Jia Xu Wenjing Luo Heng Mei Xindi Wang Zhaozhao Chen Chenggong Li Zhongpei Huang Zhuolin Wu Yinqiang Zhang Yun Kang Qiaolin Liu |
| author_sort | Jie Zhou |
| collection | DOAJ |
| description | Background Chimeric antigen receptor (CAR)-natural killer (NK) cell therapy has demonstrated safety and feasibility in clinical settings; however, limited efficacy due to intrinsic dysfunction and extrinsic suppression remains an unresolved issue. T cells provide multifaceted support to NK cell-mediated responses. Here, we aimed to design a novel CD19-targeted CAR-NK, engineered with secreted interleukin-15 and C-C motif chemokine ligand 21 (ie, 15×21 CAR-NK), capable of recruiting and cooperating with T cells.Methods We characterized 15×21 CAR-NK cells by performing experiments in vitro and in mouse models, and conducting RNA sequencing.Results 15×21 CAR-NK cells exhibit strong capabilities in cytotoxicity, cytokine production, effector molecule expression, and T-cell recruitment in vitro. Cooperation with T cells promoted efficient tumor-cell elimination, alleviated mutual exhaustion phenotypes, and enhanced the expression of effector molecules/receptors. The recruitment and cooperative effects also result in effective tumor control in mouse models. In addition, 15×21 CAR-NK cells strongly enrich the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway - a key intracellular signaling cascade that is associated with enhanced downstream pro-survival signaling, anti-apoptotic ability, mitochondrial function, and cytotoxicity.Conclusions Our study highlights the intrinsic advantages and extrinsic T-cell cooperative benefits of 15×21 CAR-NK cells, providing a promising strategy for NK-cell-based immunotherapy. |
| format | Article |
| id | doaj-art-c9cfc013e4544667828d87bbb03869d1 |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-c9cfc013e4544667828d87bbb03869d12025-08-20T02:10:21ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-06-0113610.1136/jitc-2024-010822Co-expression of IL-15 and CCL21 strengthens CAR-NK cells to eliminate tumors in concert with T cells and equips them with PI3K/AKT/mTOR signal signatureJie Zhou0Lu Tang1Yu Hu2Jun Deng3Yingying Li4Wei Xiong5Jianghua Wu6Jia Xu7Wenjing Luo8Heng Mei9Xindi Wang10Zhaozhao Chen11Chenggong Li12Zhongpei Huang13Zhuolin Wu14Yinqiang Zhang15Yun Kang16Qiaolin Liu171 Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, ChinaDepartment of Stomatology, PLA 960th Hospital, Jinan, Shandong, ChinaKey Laboratory of Biological Targeted Therapy (Huazhong University of Science and Technology), Ministry of Education, Wuhan, Hubei, ChinaHubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, Hubei, ChinaInstitute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, ChinaHubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, Hubei, ChinaDepartment of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, ChinaDepartment of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People`s Republic of China29 Department of Neurology, Wuhan General Hospital of PLA, Wuhan, ChinaKey Laboratory of Biological Targeted Therapy (Huazhong University of Science and Technology), Ministry of Education, Wuhan, Hubei, ChinaInstitute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, ChinaInstitute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, ChinaInstitute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, ChinaHubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, Hubei, ChinaInstitute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, ChinaInstitute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, ChinaInstitute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, ChinaInstitute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, ChinaBackground Chimeric antigen receptor (CAR)-natural killer (NK) cell therapy has demonstrated safety and feasibility in clinical settings; however, limited efficacy due to intrinsic dysfunction and extrinsic suppression remains an unresolved issue. T cells provide multifaceted support to NK cell-mediated responses. Here, we aimed to design a novel CD19-targeted CAR-NK, engineered with secreted interleukin-15 and C-C motif chemokine ligand 21 (ie, 15×21 CAR-NK), capable of recruiting and cooperating with T cells.Methods We characterized 15×21 CAR-NK cells by performing experiments in vitro and in mouse models, and conducting RNA sequencing.Results 15×21 CAR-NK cells exhibit strong capabilities in cytotoxicity, cytokine production, effector molecule expression, and T-cell recruitment in vitro. Cooperation with T cells promoted efficient tumor-cell elimination, alleviated mutual exhaustion phenotypes, and enhanced the expression of effector molecules/receptors. The recruitment and cooperative effects also result in effective tumor control in mouse models. In addition, 15×21 CAR-NK cells strongly enrich the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway - a key intracellular signaling cascade that is associated with enhanced downstream pro-survival signaling, anti-apoptotic ability, mitochondrial function, and cytotoxicity.Conclusions Our study highlights the intrinsic advantages and extrinsic T-cell cooperative benefits of 15×21 CAR-NK cells, providing a promising strategy for NK-cell-based immunotherapy.https://jitc.bmj.com/content/13/6/e010822.full |
| spellingShingle | Jie Zhou Lu Tang Yu Hu Jun Deng Yingying Li Wei Xiong Jianghua Wu Jia Xu Wenjing Luo Heng Mei Xindi Wang Zhaozhao Chen Chenggong Li Zhongpei Huang Zhuolin Wu Yinqiang Zhang Yun Kang Qiaolin Liu Co-expression of IL-15 and CCL21 strengthens CAR-NK cells to eliminate tumors in concert with T cells and equips them with PI3K/AKT/mTOR signal signature Journal for ImmunoTherapy of Cancer |
| title | Co-expression of IL-15 and CCL21 strengthens CAR-NK cells to eliminate tumors in concert with T cells and equips them with PI3K/AKT/mTOR signal signature |
| title_full | Co-expression of IL-15 and CCL21 strengthens CAR-NK cells to eliminate tumors in concert with T cells and equips them with PI3K/AKT/mTOR signal signature |
| title_fullStr | Co-expression of IL-15 and CCL21 strengthens CAR-NK cells to eliminate tumors in concert with T cells and equips them with PI3K/AKT/mTOR signal signature |
| title_full_unstemmed | Co-expression of IL-15 and CCL21 strengthens CAR-NK cells to eliminate tumors in concert with T cells and equips them with PI3K/AKT/mTOR signal signature |
| title_short | Co-expression of IL-15 and CCL21 strengthens CAR-NK cells to eliminate tumors in concert with T cells and equips them with PI3K/AKT/mTOR signal signature |
| title_sort | co expression of il 15 and ccl21 strengthens car nk cells to eliminate tumors in concert with t cells and equips them with pi3k akt mtor signal signature |
| url | https://jitc.bmj.com/content/13/6/e010822.full |
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