Off-the-shelf CAR-NK cells targeting immunogenic cell death marker ERp57 execute robust antitumor activity and have a synergistic effect with ICD inducer oxaliplatin
Background Chimeric antigen receptor natural killer (CAR-NK) therapy holds great promise for treating hematologic tumors, but its efficacy in solid tumors is limited owing to the lack of suitable targets and poor infiltration of engineered NK cells. Here, we explore whether immunogenic cell death (I...
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BMJ Publishing Group
2024-07-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/7/e008888.full |
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| author | Jichao Sun Dinglan Wu Liuhai Zheng Huifang Wang Jihao Zhou Guangwei Shi Jingbo Ma Yuke Jiang Zhiyu Dong Jiexuan Li Yuan-Qiao He Chengchao Xu Zhijie Li Jigang Wang |
| author_facet | Jichao Sun Dinglan Wu Liuhai Zheng Huifang Wang Jihao Zhou Guangwei Shi Jingbo Ma Yuke Jiang Zhiyu Dong Jiexuan Li Yuan-Qiao He Chengchao Xu Zhijie Li Jigang Wang |
| author_sort | Jichao Sun |
| collection | DOAJ |
| description | Background Chimeric antigen receptor natural killer (CAR-NK) therapy holds great promise for treating hematologic tumors, but its efficacy in solid tumors is limited owing to the lack of suitable targets and poor infiltration of engineered NK cells. Here, we explore whether immunogenic cell death (ICD) marker ERp57 translocated from endoplasmic reticulum to cell surface after drug treatment could be used as a target for CAR-NK therapy.Methods To target ERp57, a VHH phage display library was used for screening ERp57-targeted nanobodies (Nbs). A candidate Nb with high binding affinity to both human and mouse ERp57 was used for constructing CAR-NK cells. Various in vitro and in vivo studies were performed to assess the antitumor efficacy of the constructed CAR-NK cells.Results We demonstrate that the translocation of ERp57 can not only be induced by low-dose oxaliplatin (OXP) treatment but also is spontaneously expressed on the surface of various types of tumor cell lines. Our results show that G6-CAR-NK92 cells can effectively kill various tumor cell lines in vitro on which ERp57 is induced or intrinsically expressed, and also exhibit potent antitumor effects in cancer cell-derived xenograft and patient-derived xenograft mouse models. Additionally, the antitumor activity of G6-CAR-NK92 cells is synergistically enhanced by the low-dose ICD-inducible drug OXP.Conclusion Collectively, our findings suggest that ERp57 can be leveraged as a new tumor antigen for CAR-NK targeting, and the resultant CAR-NK cells have the potential to be applied as a broad-spectrum immune cell therapy for various cancers by combining with ICD inducer drugs. |
| format | Article |
| id | doaj-art-0da42825ed99483b9d8be09956ef2809 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-07-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-0da42825ed99483b9d8be09956ef28092025-02-09T18:05:14ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-07-0112710.1136/jitc-2024-008888Off-the-shelf CAR-NK cells targeting immunogenic cell death marker ERp57 execute robust antitumor activity and have a synergistic effect with ICD inducer oxaliplatinJichao Sun0Dinglan Wu1Liuhai Zheng2Huifang Wang3Jihao Zhou4Guangwei Shi5Jingbo Ma6Yuke Jiang7Zhiyu Dong8Jiexuan Li9Yuan-Qiao He10Chengchao Xu11Zhijie Li12Jigang Wang131 Department of Geriatrics and Shenzhen Clinical Research Centre for Geriatrics, Department of Urology, Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, ChinaShenzhen Key Laboratory of Viral Oncology, The Clinical Innovation & Research Centre, Shenzhen Hospital of Southern Medical University, Shenzhen, Guangdong, People`s Republic of China1 Department of Geriatrics and Shenzhen Clinical Research Centre for Geriatrics, Department of Urology, Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, China1 Department of Geriatrics and Shenzhen Clinical Research Centre for Geriatrics, Department of Urology, Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, China1 Department of Geriatrics and Shenzhen Clinical Research Centre for Geriatrics, Department of Urology, Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, China1 Department of Geriatrics and Shenzhen Clinical Research Centre for Geriatrics, Department of Urology, Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, China1 Department of Geriatrics and Shenzhen Clinical Research Centre for Geriatrics, Department of Urology, Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, China1 Department of Geriatrics and Shenzhen Clinical Research Centre for Geriatrics, Department of Urology, Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, China1 Department of Geriatrics and Shenzhen Clinical Research Centre for Geriatrics, Department of Urology, Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, China1 Department of Geriatrics and Shenzhen Clinical Research Centre for Geriatrics, Department of Urology, Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, China5 Center of Laboratory Animal Science, Nanchang University, Nanchang, Jiangxi, China1 Department of Geriatrics and Shenzhen Clinical Research Centre for Geriatrics, Department of Urology, Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, China1 Department of Geriatrics and Shenzhen Clinical Research Centre for Geriatrics, Department of Urology, Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, China1 Department of Geriatrics and Shenzhen Clinical Research Centre for Geriatrics, Department of Urology, Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, ChinaBackground Chimeric antigen receptor natural killer (CAR-NK) therapy holds great promise for treating hematologic tumors, but its efficacy in solid tumors is limited owing to the lack of suitable targets and poor infiltration of engineered NK cells. Here, we explore whether immunogenic cell death (ICD) marker ERp57 translocated from endoplasmic reticulum to cell surface after drug treatment could be used as a target for CAR-NK therapy.Methods To target ERp57, a VHH phage display library was used for screening ERp57-targeted nanobodies (Nbs). A candidate Nb with high binding affinity to both human and mouse ERp57 was used for constructing CAR-NK cells. Various in vitro and in vivo studies were performed to assess the antitumor efficacy of the constructed CAR-NK cells.Results We demonstrate that the translocation of ERp57 can not only be induced by low-dose oxaliplatin (OXP) treatment but also is spontaneously expressed on the surface of various types of tumor cell lines. Our results show that G6-CAR-NK92 cells can effectively kill various tumor cell lines in vitro on which ERp57 is induced or intrinsically expressed, and also exhibit potent antitumor effects in cancer cell-derived xenograft and patient-derived xenograft mouse models. Additionally, the antitumor activity of G6-CAR-NK92 cells is synergistically enhanced by the low-dose ICD-inducible drug OXP.Conclusion Collectively, our findings suggest that ERp57 can be leveraged as a new tumor antigen for CAR-NK targeting, and the resultant CAR-NK cells have the potential to be applied as a broad-spectrum immune cell therapy for various cancers by combining with ICD inducer drugs.https://jitc.bmj.com/content/12/7/e008888.full |
| spellingShingle | Jichao Sun Dinglan Wu Liuhai Zheng Huifang Wang Jihao Zhou Guangwei Shi Jingbo Ma Yuke Jiang Zhiyu Dong Jiexuan Li Yuan-Qiao He Chengchao Xu Zhijie Li Jigang Wang Off-the-shelf CAR-NK cells targeting immunogenic cell death marker ERp57 execute robust antitumor activity and have a synergistic effect with ICD inducer oxaliplatin Journal for ImmunoTherapy of Cancer |
| title | Off-the-shelf CAR-NK cells targeting immunogenic cell death marker ERp57 execute robust antitumor activity and have a synergistic effect with ICD inducer oxaliplatin |
| title_full | Off-the-shelf CAR-NK cells targeting immunogenic cell death marker ERp57 execute robust antitumor activity and have a synergistic effect with ICD inducer oxaliplatin |
| title_fullStr | Off-the-shelf CAR-NK cells targeting immunogenic cell death marker ERp57 execute robust antitumor activity and have a synergistic effect with ICD inducer oxaliplatin |
| title_full_unstemmed | Off-the-shelf CAR-NK cells targeting immunogenic cell death marker ERp57 execute robust antitumor activity and have a synergistic effect with ICD inducer oxaliplatin |
| title_short | Off-the-shelf CAR-NK cells targeting immunogenic cell death marker ERp57 execute robust antitumor activity and have a synergistic effect with ICD inducer oxaliplatin |
| title_sort | off the shelf car nk cells targeting immunogenic cell death marker erp57 execute robust antitumor activity and have a synergistic effect with icd inducer oxaliplatin |
| url | https://jitc.bmj.com/content/12/7/e008888.full |
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