Metabolic radiolabeling and in vivo PET imaging of cytotoxic T lymphocytes to guide combination adoptive cell transfer cancer therapy
Abstract Background Adoptive T cell transfer-based immunotherapy yields unsatisfactory results in the treatment of solid tumors, partially owing to limited tumor infiltration and the immunosuppressive microenvironment in solid tumors. Therefore, strategies for the noninvasive tracking of adoptive T...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-06-01
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| Series: | Journal of Nanobiotechnology |
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| Online Access: | https://doi.org/10.1186/s12951-021-00924-2 |
| _version_ | 1828179881193635840 |
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| author | Dehua Lu Yanpu Wang Ting Zhang Feng Wang Kui Li Shixin Zhou Hua Zhu Zhi Yang Zhaofei Liu |
| author_facet | Dehua Lu Yanpu Wang Ting Zhang Feng Wang Kui Li Shixin Zhou Hua Zhu Zhi Yang Zhaofei Liu |
| author_sort | Dehua Lu |
| collection | DOAJ |
| description | Abstract Background Adoptive T cell transfer-based immunotherapy yields unsatisfactory results in the treatment of solid tumors, partially owing to limited tumor infiltration and the immunosuppressive microenvironment in solid tumors. Therefore, strategies for the noninvasive tracking of adoptive T cells are critical for monitoring tumor infiltration and for guiding the development of novel combination therapies. Methods We developed a radiolabeling method for cytotoxic T lymphocytes (CTLs) that comprises metabolically labeling the cell surface glycans with azidosugars and then covalently conjugating them with 64Cu-1,4,7-triazacyclononanetriacetic acid-dibenzo-cyclooctyne (64Cu-NOTA-DBCO) using bioorthogonal chemistry. 64Cu-labeled control-CTLs and ovalbumin-specific CTLs (OVA-CTLs) were tracked using positron emission tomography (PET) in B16-OVA tumor-bearing mice. We also investigated the effects of focal adhesion kinase (FAK) inhibition on the antitumor efficacy of OVA-CTLs using a poly(lactic-co-glycolic) acid (PLGA)-encapsulated nanodrug (PLGA-FAKi). Results CTLs can be stably radiolabeled with 64Cu with a minimal effect on cell viability. PET imaging of 64Cu-OVA-CTLs enables noninvasive mapping of their in vivo behavior. Moreover, 64Cu-OVA-CTLs PET imaging revealed that PLGA-FAKi induced a significant increase in OVA-CTL infiltration into tumors, suggesting the potential for a combined therapy comprising OVA-CTLs and PLGA-FAKi. Further combination therapy studies confirmed that the PLGA-FAKi nanodrug markedly improved the antitumor effects of adoptive OVA-CTLs transfer by multiple mechanisms. Conclusion These findings demonstrated that metabolic radiolabeling followed by PET imaging can be used to sensitively profile the early-stage migration and tumor-targeting efficiency of adoptive T cells in vivo. This strategy presents opportunities for predicting the efficacy of cell-based adoptive therapies and for guiding combination regimens. Graphic Abstract |
| first_indexed | 2024-04-12T05:35:57Z |
| format | Article |
| id | doaj.art-b1ddf2b2efcc458aa4457aaa195f2531 |
| institution | Directory Open Access Journal |
| issn | 1477-3155 |
| language | English |
| last_indexed | 2024-04-12T05:35:57Z |
| publishDate | 2021-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj.art-b1ddf2b2efcc458aa4457aaa195f25312022-12-22T03:45:51ZengBMCJournal of Nanobiotechnology1477-31552021-06-0119111410.1186/s12951-021-00924-2Metabolic radiolabeling and in vivo PET imaging of cytotoxic T lymphocytes to guide combination adoptive cell transfer cancer therapyDehua Lu0Yanpu Wang1Ting Zhang2Feng Wang3Kui Li4Shixin Zhou5Hua Zhu6Zhi Yang7Zhaofei Liu8Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science CenterMedical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science CenterMedical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science CenterKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & InstituteMedical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science CenterDepartment of Cell Biology, School of Basic Medical Sciences, Peking University Health Science CenterKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & InstituteMedical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science CenterAbstract Background Adoptive T cell transfer-based immunotherapy yields unsatisfactory results in the treatment of solid tumors, partially owing to limited tumor infiltration and the immunosuppressive microenvironment in solid tumors. Therefore, strategies for the noninvasive tracking of adoptive T cells are critical for monitoring tumor infiltration and for guiding the development of novel combination therapies. Methods We developed a radiolabeling method for cytotoxic T lymphocytes (CTLs) that comprises metabolically labeling the cell surface glycans with azidosugars and then covalently conjugating them with 64Cu-1,4,7-triazacyclononanetriacetic acid-dibenzo-cyclooctyne (64Cu-NOTA-DBCO) using bioorthogonal chemistry. 64Cu-labeled control-CTLs and ovalbumin-specific CTLs (OVA-CTLs) were tracked using positron emission tomography (PET) in B16-OVA tumor-bearing mice. We also investigated the effects of focal adhesion kinase (FAK) inhibition on the antitumor efficacy of OVA-CTLs using a poly(lactic-co-glycolic) acid (PLGA)-encapsulated nanodrug (PLGA-FAKi). Results CTLs can be stably radiolabeled with 64Cu with a minimal effect on cell viability. PET imaging of 64Cu-OVA-CTLs enables noninvasive mapping of their in vivo behavior. Moreover, 64Cu-OVA-CTLs PET imaging revealed that PLGA-FAKi induced a significant increase in OVA-CTL infiltration into tumors, suggesting the potential for a combined therapy comprising OVA-CTLs and PLGA-FAKi. Further combination therapy studies confirmed that the PLGA-FAKi nanodrug markedly improved the antitumor effects of adoptive OVA-CTLs transfer by multiple mechanisms. Conclusion These findings demonstrated that metabolic radiolabeling followed by PET imaging can be used to sensitively profile the early-stage migration and tumor-targeting efficiency of adoptive T cells in vivo. This strategy presents opportunities for predicting the efficacy of cell-based adoptive therapies and for guiding combination regimens. Graphic Abstracthttps://doi.org/10.1186/s12951-021-00924-2Positron emission tomographyRadiolabelingAdoptive cell transferFocal adhesion kinase inhibitionImage-guided therapy |
| spellingShingle | Dehua Lu Yanpu Wang Ting Zhang Feng Wang Kui Li Shixin Zhou Hua Zhu Zhi Yang Zhaofei Liu Metabolic radiolabeling and in vivo PET imaging of cytotoxic T lymphocytes to guide combination adoptive cell transfer cancer therapy Journal of Nanobiotechnology Positron emission tomography Radiolabeling Adoptive cell transfer Focal adhesion kinase inhibition Image-guided therapy |
| title | Metabolic radiolabeling and in vivo PET imaging of cytotoxic T lymphocytes to guide combination adoptive cell transfer cancer therapy |
| title_full | Metabolic radiolabeling and in vivo PET imaging of cytotoxic T lymphocytes to guide combination adoptive cell transfer cancer therapy |
| title_fullStr | Metabolic radiolabeling and in vivo PET imaging of cytotoxic T lymphocytes to guide combination adoptive cell transfer cancer therapy |
| title_full_unstemmed | Metabolic radiolabeling and in vivo PET imaging of cytotoxic T lymphocytes to guide combination adoptive cell transfer cancer therapy |
| title_short | Metabolic radiolabeling and in vivo PET imaging of cytotoxic T lymphocytes to guide combination adoptive cell transfer cancer therapy |
| title_sort | metabolic radiolabeling and in vivo pet imaging of cytotoxic t lymphocytes to guide combination adoptive cell transfer cancer therapy |
| topic | Positron emission tomography Radiolabeling Adoptive cell transfer Focal adhesion kinase inhibition Image-guided therapy |
| url | https://doi.org/10.1186/s12951-021-00924-2 |
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