Efficacy of natural killer T and gammadelta T cells in mesothelin-targeted immunotherapy of pancreatic cancer
Current pancreatic cancer immunotherapy focused on alphabeta (αβ) T cells, either through CD3-engaged bispecific antibodies or CAR-T. Despite their promise, dose-limited toxicity (DLT) remains a challenge in clinical practice. In light of these concerns, there is a growing interest in exploring alte...
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1524899/full |
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| author | Yuankui Zhu Yaxi Yang Linghe Yue Lei Wan Xuqian Ma Qing Yang Xuan Tian Yuguan Li Ke Wang Shaozhong Wei Shaozhong Wei Shaozhong Wei Dianbao Zuo Mingqian Feng Mingqian Feng |
| author_facet | Yuankui Zhu Yaxi Yang Linghe Yue Lei Wan Xuqian Ma Qing Yang Xuan Tian Yuguan Li Ke Wang Shaozhong Wei Shaozhong Wei Shaozhong Wei Dianbao Zuo Mingqian Feng Mingqian Feng |
| author_sort | Yuankui Zhu |
| collection | DOAJ |
| description | Current pancreatic cancer immunotherapy focused on alphabeta (αβ) T cells, either through CD3-engaged bispecific antibodies or CAR-T. Despite their promise, dose-limited toxicity (DLT) remains a challenge in clinical practice. In light of these concerns, there is a growing interest in exploring alternative T cell types, natural killer T (NKT) cells and gammadelta (γδ) T cells, that possess the capacity to lyse tumors while potentially offering a safer therapeutic profile with fewer side effects. These cells present a compelling alternative that warrants a comprehensive evaluation of their therapeutic potential and safety profile. This study employed a MSLN/CD3 bispecific antibody to compare the anti-tumor activity of NKT and γδT cells with peripheral blood mononuclear cells (PBMCs) as controls, both in vitro and in vivo. This study demonstrated that MSLN/CD3 BsAb effectively activated and recruited PBMCs, NKT and γδT. Furthermore, under the influence of MSLN/CD3 BsAb, γδT and NKT cells exhibited notably superior anti-tumor activity compared to PBMCs, both in vitro and in vivo, while demonstrating low cytokine release. γδT cells showed almost negligible toxic side effects. In addition, the systemic administration of NKT and γδT cells activators, α-galactosylceramide (α-GalCer) and Zoledronate, could enhance the anti-tumor effect of MSLN/CD3 bsAb, with no apparent toxicity. NKT and γδT cells are promising synergistic therapeutic cell types that may overcome the limitations of CD3 bispecific antibodies in pancreatic tumor treatments, offering a new perspective for clinical applications in immunotherapy. |
| format | Article |
| id | doaj-art-990f47d4b8b84fb0947284228fa7031a |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-990f47d4b8b84fb0947284228fa7031a2025-02-10T06:49:03ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-02-011610.3389/fimmu.2025.15248991524899Efficacy of natural killer T and gammadelta T cells in mesothelin-targeted immunotherapy of pancreatic cancerYuankui Zhu0Yaxi Yang1Linghe Yue2Lei Wan3Xuqian Ma4Qing Yang5Xuan Tian6Yuguan Li7Ke Wang8Shaozhong Wei9Shaozhong Wei10Shaozhong Wei11Dianbao Zuo12Mingqian Feng13Mingqian Feng14College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, Hubei, ChinaCollege of Biomedicine and Health, Huazhong Agricultural University, Wuhan, Hubei, ChinaCollege of Biomedicine and Health, Huazhong Agricultural University, Wuhan, Hubei, ChinaCollege of Biomedicine and Health, Huazhong Agricultural University, Wuhan, Hubei, ChinaCollege of Biomedicine and Health, Huazhong Agricultural University, Wuhan, Hubei, ChinaCollege of Biomedicine and Health, Huazhong Agricultural University, Wuhan, Hubei, ChinaCollege of Biomedicine and Health, Huazhong Agricultural University, Wuhan, Hubei, ChinaCollege of Biomedicine and Health, Huazhong Agricultural University, Wuhan, Hubei, ChinaCollege of Biomedicine and Health, Huazhong Agricultural University, Wuhan, Hubei, ChinaDepartment of Gastrointestinal Oncology Surgery, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, ChinaDepartment of Gastrointestinal Oncology Surgery, Colorectal Cancer Clinical Research Center of Hubei Province, Wuhan, Hubei, ChinaDepartment of Gastrointestinal Oncology Surgery, Colorectal Cancer Clinical Research Center of Wuhan, Wuhan, Hubei, ChinaResearch Center for Translational Medicine, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei Provincial Clinical Research Center for Parkinson’s Disease at Xiangyang No.1 People’s Hospital, Hubei University of Medicine, Xiangyang, ChinaCollege of Biomedicine and Health, Huazhong Agricultural University, Wuhan, Hubei, ChinaCollege of Life Science & Technology, Huazhong Agricultural University, Wuhan, Hubei, ChinaCurrent pancreatic cancer immunotherapy focused on alphabeta (αβ) T cells, either through CD3-engaged bispecific antibodies or CAR-T. Despite their promise, dose-limited toxicity (DLT) remains a challenge in clinical practice. In light of these concerns, there is a growing interest in exploring alternative T cell types, natural killer T (NKT) cells and gammadelta (γδ) T cells, that possess the capacity to lyse tumors while potentially offering a safer therapeutic profile with fewer side effects. These cells present a compelling alternative that warrants a comprehensive evaluation of their therapeutic potential and safety profile. This study employed a MSLN/CD3 bispecific antibody to compare the anti-tumor activity of NKT and γδT cells with peripheral blood mononuclear cells (PBMCs) as controls, both in vitro and in vivo. This study demonstrated that MSLN/CD3 BsAb effectively activated and recruited PBMCs, NKT and γδT. Furthermore, under the influence of MSLN/CD3 BsAb, γδT and NKT cells exhibited notably superior anti-tumor activity compared to PBMCs, both in vitro and in vivo, while demonstrating low cytokine release. γδT cells showed almost negligible toxic side effects. In addition, the systemic administration of NKT and γδT cells activators, α-galactosylceramide (α-GalCer) and Zoledronate, could enhance the anti-tumor effect of MSLN/CD3 bsAb, with no apparent toxicity. NKT and γδT cells are promising synergistic therapeutic cell types that may overcome the limitations of CD3 bispecific antibodies in pancreatic tumor treatments, offering a new perspective for clinical applications in immunotherapy.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1524899/fullNKTγδTPBMCsbispecific antibodypancreatic tumor |
| spellingShingle | Yuankui Zhu Yaxi Yang Linghe Yue Lei Wan Xuqian Ma Qing Yang Xuan Tian Yuguan Li Ke Wang Shaozhong Wei Shaozhong Wei Shaozhong Wei Dianbao Zuo Mingqian Feng Mingqian Feng Efficacy of natural killer T and gammadelta T cells in mesothelin-targeted immunotherapy of pancreatic cancer Frontiers in Immunology NKT γδT PBMCs bispecific antibody pancreatic tumor |
| title | Efficacy of natural killer T and gammadelta T cells in mesothelin-targeted immunotherapy of pancreatic cancer |
| title_full | Efficacy of natural killer T and gammadelta T cells in mesothelin-targeted immunotherapy of pancreatic cancer |
| title_fullStr | Efficacy of natural killer T and gammadelta T cells in mesothelin-targeted immunotherapy of pancreatic cancer |
| title_full_unstemmed | Efficacy of natural killer T and gammadelta T cells in mesothelin-targeted immunotherapy of pancreatic cancer |
| title_short | Efficacy of natural killer T and gammadelta T cells in mesothelin-targeted immunotherapy of pancreatic cancer |
| title_sort | efficacy of natural killer t and gammadelta t cells in mesothelin targeted immunotherapy of pancreatic cancer |
| topic | NKT γδT PBMCs bispecific antibody pancreatic tumor |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1524899/full |
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