Noninvasive Immunotyping and Immunotherapy Monitoring of Lung Cancers via Nuclear Imaging of LAG‐3 and PD‐L1
Abstract Immunotherapy has significantly improved cancer patient survival, while its efficacy remains limited due to the reliance on a single marker like PD‐L1 as well as its spatiotemporal heterogeneity. To address this issue, combining lymphocyte activation gene‐3 (LAG‐3) with PD‐L1 is proposed fo...
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| Format: | Article |
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Wiley
2025-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202404231 |
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| author | Lishu Zhao Jianxian Ge Ruru Zhang Hao Wang Xinyue Liu Kandi Xu Yujin Liu Wencheng Zhao Wengang Zhang Li Ye Zhimin Chen Jianfeng Zeng Yayi He Mingyuan Gao |
| author_facet | Lishu Zhao Jianxian Ge Ruru Zhang Hao Wang Xinyue Liu Kandi Xu Yujin Liu Wencheng Zhao Wengang Zhang Li Ye Zhimin Chen Jianfeng Zeng Yayi He Mingyuan Gao |
| author_sort | Lishu Zhao |
| collection | DOAJ |
| description | Abstract Immunotherapy has significantly improved cancer patient survival, while its efficacy remains limited due to the reliance on a single marker like PD‐L1 as well as its spatiotemporal heterogeneity. To address this issue, combining lymphocyte activation gene‐3 (LAG‐3) with PD‐L1 is proposed for identifying immunotypes and monitoring immunotherapy through nuclear imaging. In short, 99mTc‐HYNIC‐αLAG‐3 and 99mTc‐HYNIC‐αPD‐L1 probes are synthesized using anti‐human LAG‐3 and PD‐L1 antibodies, respectively. With high radiochemical purity and in vitro stability, these probes are confirmed to specifically bind to LAG‐3 or PD‐L1 in LAG3+ A549, LAG3− A549, and H1975 cells. SPECT/CT imaging of both probes showed specific in vivo tumor uptake in multiple lung cancer models, with significant linear correlation with ex vivo tumor uptake and immunohistochemical expression levels of LAG‐3/PD‐L1. Based on this, dual‐index imaging was performed to simultaneously quantify LAG‐3 and PD‐L1. SPECT/CT imaging of 99mTc‐HYNIC‐αLAG‐3 and 125I‐αPD‐L1 successfully distinguished four immunotypes. In addition, SPECT/CT imaging revealed LAG‐3 upregulation in LLC‐bearing LAG‐3 humanized mice resistant to immunotherapy. In conclusion, this study demonstrates the feasibility of nuclear imaging of LAG‐3 and PD‐L1 for both noninvasive immunotyping and immunotherapy monitoring, thus offering novel perspectives on forecasting immunotherapy response, uncovering resistance mechanism, and optimizing combination treatment regimens. |
| format | Article |
| id | doaj-art-5abcc46e18a942e4b53bf97b6d455778 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-5abcc46e18a942e4b53bf97b6d4557782025-01-09T11:44:45ZengWileyAdvanced Science2198-38442025-01-01121n/an/a10.1002/advs.202404231Noninvasive Immunotyping and Immunotherapy Monitoring of Lung Cancers via Nuclear Imaging of LAG‐3 and PD‐L1Lishu Zhao0Jianxian Ge1Ruru Zhang2Hao Wang3Xinyue Liu4Kandi Xu5Yujin Liu6Wencheng Zhao7Wengang Zhang8Li Ye9Zhimin Chen10Jianfeng Zeng11Yayi He12Mingyuan Gao13Department of Medical Oncology Shanghai Pulmonary Hospital Tongji University Medical School Cancer Institute School of Medicine Tongji University No 507 Zhengmin Road Shanghai 200433 ChinaCenter for Molecular Imaging and Nuclear Medicine State Key Laboratory of Radiation Medicine and Protection School for Radiological and Interdisciplinary Sciences (RAD‐X) Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions Soochow University Suzhou 215123 ChinaCenter for Molecular Imaging and Nuclear Medicine State Key Laboratory of Radiation Medicine and Protection School for Radiological and Interdisciplinary Sciences (RAD‐X) Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions Soochow University Suzhou 215123 ChinaDepartment of Medical Oncology Shanghai Pulmonary Hospital Tongji University Medical School Cancer Institute School of Medicine Tongji University No 507 Zhengmin Road Shanghai 200433 ChinaDepartment of Medical Oncology Shanghai Pulmonary Hospital Tongji University Medical School Cancer Institute School of Medicine Tongji University No 507 Zhengmin Road Shanghai 200433 ChinaDepartment of Medical Oncology Shanghai Pulmonary Hospital Tongji University Medical School Cancer Institute School of Medicine Tongji University No 507 Zhengmin Road Shanghai 200433 ChinaDepartment of Medical Oncology Shanghai Pulmonary Hospital Tongji University Medical School Cancer Institute School of Medicine Tongji University No 507 Zhengmin Road Shanghai 200433 ChinaDepartment of Medical Oncology Shanghai Pulmonary Hospital Tongji University Medical School Cancer Institute School of Medicine Tongji University No 507 Zhengmin Road Shanghai 200433 ChinaDepartment of Medical Oncology Shanghai Pulmonary Hospital Tongji University Medical School Cancer Institute School of Medicine Tongji University No 507 Zhengmin Road Shanghai 200433 ChinaDepartment of Medical Oncology Shanghai Pulmonary Hospital Tongji University Medical School Cancer Institute School of Medicine Tongji University No 507 Zhengmin Road Shanghai 200433 ChinaDepartment of Medical Oncology Shanghai Pulmonary Hospital Tongji University Medical School Cancer Institute School of Medicine Tongji University No 507 Zhengmin Road Shanghai 200433 ChinaCenter for Molecular Imaging and Nuclear Medicine State Key Laboratory of Radiation Medicine and Protection School for Radiological and Interdisciplinary Sciences (RAD‐X) Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions Soochow University Suzhou 215123 ChinaDepartment of Medical Oncology Shanghai Pulmonary Hospital Tongji University Medical School Cancer Institute School of Medicine Tongji University No 507 Zhengmin Road Shanghai 200433 ChinaCenter for Molecular Imaging and Nuclear Medicine State Key Laboratory of Radiation Medicine and Protection School for Radiological and Interdisciplinary Sciences (RAD‐X) Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions Soochow University Suzhou 215123 ChinaAbstract Immunotherapy has significantly improved cancer patient survival, while its efficacy remains limited due to the reliance on a single marker like PD‐L1 as well as its spatiotemporal heterogeneity. To address this issue, combining lymphocyte activation gene‐3 (LAG‐3) with PD‐L1 is proposed for identifying immunotypes and monitoring immunotherapy through nuclear imaging. In short, 99mTc‐HYNIC‐αLAG‐3 and 99mTc‐HYNIC‐αPD‐L1 probes are synthesized using anti‐human LAG‐3 and PD‐L1 antibodies, respectively. With high radiochemical purity and in vitro stability, these probes are confirmed to specifically bind to LAG‐3 or PD‐L1 in LAG3+ A549, LAG3− A549, and H1975 cells. SPECT/CT imaging of both probes showed specific in vivo tumor uptake in multiple lung cancer models, with significant linear correlation with ex vivo tumor uptake and immunohistochemical expression levels of LAG‐3/PD‐L1. Based on this, dual‐index imaging was performed to simultaneously quantify LAG‐3 and PD‐L1. SPECT/CT imaging of 99mTc‐HYNIC‐αLAG‐3 and 125I‐αPD‐L1 successfully distinguished four immunotypes. In addition, SPECT/CT imaging revealed LAG‐3 upregulation in LLC‐bearing LAG‐3 humanized mice resistant to immunotherapy. In conclusion, this study demonstrates the feasibility of nuclear imaging of LAG‐3 and PD‐L1 for both noninvasive immunotyping and immunotherapy monitoring, thus offering novel perspectives on forecasting immunotherapy response, uncovering resistance mechanism, and optimizing combination treatment regimens.https://doi.org/10.1002/advs.202404231lung cancernuclear imagingSPECTLAG‐3PD‐L1immunotherapy |
| spellingShingle | Lishu Zhao Jianxian Ge Ruru Zhang Hao Wang Xinyue Liu Kandi Xu Yujin Liu Wencheng Zhao Wengang Zhang Li Ye Zhimin Chen Jianfeng Zeng Yayi He Mingyuan Gao Noninvasive Immunotyping and Immunotherapy Monitoring of Lung Cancers via Nuclear Imaging of LAG‐3 and PD‐L1 Advanced Science lung cancer nuclear imaging SPECT LAG‐3 PD‐L1 immunotherapy |
| title | Noninvasive Immunotyping and Immunotherapy Monitoring of Lung Cancers via Nuclear Imaging of LAG‐3 and PD‐L1 |
| title_full | Noninvasive Immunotyping and Immunotherapy Monitoring of Lung Cancers via Nuclear Imaging of LAG‐3 and PD‐L1 |
| title_fullStr | Noninvasive Immunotyping and Immunotherapy Monitoring of Lung Cancers via Nuclear Imaging of LAG‐3 and PD‐L1 |
| title_full_unstemmed | Noninvasive Immunotyping and Immunotherapy Monitoring of Lung Cancers via Nuclear Imaging of LAG‐3 and PD‐L1 |
| title_short | Noninvasive Immunotyping and Immunotherapy Monitoring of Lung Cancers via Nuclear Imaging of LAG‐3 and PD‐L1 |
| title_sort | noninvasive immunotyping and immunotherapy monitoring of lung cancers via nuclear imaging of lag 3 and pd l1 |
| topic | lung cancer nuclear imaging SPECT LAG‐3 PD‐L1 immunotherapy |
| url | https://doi.org/10.1002/advs.202404231 |
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