Implication of 99mTc-sum IL-2 SPECT/CT in immunotherapy by imaging of tumor-infiltrating T cells
Background Although immune checkpoint blockade (ICB) and adoptive T cell transfer (ACT) therapy have achieved impressive clinical outcomes, majority of patients do not respond to immunotherapy. Tumor-infiltrating T cells, a critical factor to immunotherapy, is dynamically changing. Therefore, a reli...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2023-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/3/e005925.full |
| _version_ | 1811161081663455232 |
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| author | Fan Wang Hannan Gao Jiyun Shi Yue Yu Qi Luo Yu Gao Zhichen Sun Yining Sun Xiaotu Ma Chuanhui Han |
| author_facet | Fan Wang Hannan Gao Jiyun Shi Yue Yu Qi Luo Yu Gao Zhichen Sun Yining Sun Xiaotu Ma Chuanhui Han |
| author_sort | Fan Wang |
| collection | DOAJ |
| description | Background Although immune checkpoint blockade (ICB) and adoptive T cell transfer (ACT) therapy have achieved impressive clinical outcomes, majority of patients do not respond to immunotherapy. Tumor-infiltrating T cells, a critical factor to immunotherapy, is dynamically changing. Therefore, a reliable real-time in vivo imaging system for tumor-infiltrating T cells, but not immunohistochemical analyses, will be more valuable to predict response and guide immunotherapy. In this study, we developed a new SPECT/CT imaging probe 99mTc-sum IL-2 targeting the IL-2Rβ/IL-2Rγ (CD122/CD132) receptor on tumor-infiltrating T cells, and evaluated its application in predicting the immune response to anti-PD-L1 (αPD-L1) therapy as well as tracking infused T cells in ACT therapy.Methods The binding affinity of the super mutated IL-2 (sum IL-2) in various T cell subtypes was measured. Sum IL-2 was subsequently labeled with 99mTc through Sortase-A mediated site-specific transpeptidation. SPECT/CT imaging and biodistribution studies of 99mTc-sum IL-2 were performed in a MC38 mouse model. Wild type IL-2 (IL-2) was used as control in the above studies. Finally, we evaluated 99mTc-sum IL-2 SPECT/CT for the detection of tumor-infiltrating T cells in the context of αPD-L1 immunotherapy and ACT therapy.Results Sum IL-2 preferentially bound to CD8+ T cells, especially activated CD8+ T cells, while IL-2 showed biased binding to Treg cells. As a result, 99mTc-sum IL-2 could detect tumor-infiltrating T cells. In the MC38 tumor model, SPECT/CT imaging showed the increased tumor uptake of 99mTc-sum IL-2 after αPD-L1 treatment, suggesting that the treatment significantly increased tumor-infiltrating T cells, resulting in a correspondingly significant curative effect. In addition, 99mTc-sum IL-2 SPECT/CT could also track the infiltration of antigen-specific cytotoxic CD8+ T cells during ACT therapy.Conclusion 99mTc-sum IL-2 has great clinical potential for non-invasive and specific SPECT/CT imaging of tumor-infiltrating T cells as well as for timely prediction and evaluation of the therapeutic efficacy of ICB and ACT therapy. |
| first_indexed | 2024-04-10T06:08:41Z |
| format | Article |
| id | doaj.art-ad84fce022a64279a6c58dc1361591a2 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-04-10T06:08:41Z |
| publishDate | 2023-03-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-ad84fce022a64279a6c58dc1361591a22023-03-02T21:30:13ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-03-0111310.1136/jitc-2022-005925Implication of 99mTc-sum IL-2 SPECT/CT in immunotherapy by imaging of tumor-infiltrating T cellsFan Wang0Hannan Gao1Jiyun Shi2Yue Yu3Qi Luo4Yu Gao5Zhichen Sun6Yining Sun7Xiaotu Ma8Chuanhui Han9Key Laboratory of Proteinand Peptide Pharmaceuticals, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics Chinese Academy of Sciences, Beijing, ChinaKey Laboratory of Proteinand Peptide Pharmaceuticals, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics Chinese Academy of Sciences, Beijing, ChinaKey Laboratory of Proteinand Peptide Pharmaceuticals, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics Chinese Academy of Sciences, Beijing, ChinaKey Laboratory of Proteinand Peptide Pharmaceuticals, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics Chinese Academy of Sciences, Beijing, ChinaGuangzhou Laboratory, Guangzhou, ChinaKey Laboratory of Proteinand Peptide Pharmaceuticals, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics Chinese Academy of Sciences, Beijing, ChinaKey Laboratory of Proteinand Peptide Pharmaceuticals, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics Chinese Academy of Sciences, Beijing, ChinaKey Laboratory of Proteinand Peptide Pharmaceuticals, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics Chinese Academy of Sciences, Beijing, ChinaKey Laboratory of Proteinand Peptide Pharmaceuticals, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics Chinese Academy of Sciences, Beijing, ChinaMedical Isotopes Research Center and Department of Radiation Medicine, State Key Laboratory of Natural and Biomimetic Drugs, School of Basic Medical Sciences, International Cancer Institute, Peking University, Beijing, ChinaBackground Although immune checkpoint blockade (ICB) and adoptive T cell transfer (ACT) therapy have achieved impressive clinical outcomes, majority of patients do not respond to immunotherapy. Tumor-infiltrating T cells, a critical factor to immunotherapy, is dynamically changing. Therefore, a reliable real-time in vivo imaging system for tumor-infiltrating T cells, but not immunohistochemical analyses, will be more valuable to predict response and guide immunotherapy. In this study, we developed a new SPECT/CT imaging probe 99mTc-sum IL-2 targeting the IL-2Rβ/IL-2Rγ (CD122/CD132) receptor on tumor-infiltrating T cells, and evaluated its application in predicting the immune response to anti-PD-L1 (αPD-L1) therapy as well as tracking infused T cells in ACT therapy.Methods The binding affinity of the super mutated IL-2 (sum IL-2) in various T cell subtypes was measured. Sum IL-2 was subsequently labeled with 99mTc through Sortase-A mediated site-specific transpeptidation. SPECT/CT imaging and biodistribution studies of 99mTc-sum IL-2 were performed in a MC38 mouse model. Wild type IL-2 (IL-2) was used as control in the above studies. Finally, we evaluated 99mTc-sum IL-2 SPECT/CT for the detection of tumor-infiltrating T cells in the context of αPD-L1 immunotherapy and ACT therapy.Results Sum IL-2 preferentially bound to CD8+ T cells, especially activated CD8+ T cells, while IL-2 showed biased binding to Treg cells. As a result, 99mTc-sum IL-2 could detect tumor-infiltrating T cells. In the MC38 tumor model, SPECT/CT imaging showed the increased tumor uptake of 99mTc-sum IL-2 after αPD-L1 treatment, suggesting that the treatment significantly increased tumor-infiltrating T cells, resulting in a correspondingly significant curative effect. In addition, 99mTc-sum IL-2 SPECT/CT could also track the infiltration of antigen-specific cytotoxic CD8+ T cells during ACT therapy.Conclusion 99mTc-sum IL-2 has great clinical potential for non-invasive and specific SPECT/CT imaging of tumor-infiltrating T cells as well as for timely prediction and evaluation of the therapeutic efficacy of ICB and ACT therapy.https://jitc.bmj.com/content/11/3/e005925.full |
| spellingShingle | Fan Wang Hannan Gao Jiyun Shi Yue Yu Qi Luo Yu Gao Zhichen Sun Yining Sun Xiaotu Ma Chuanhui Han Implication of 99mTc-sum IL-2 SPECT/CT in immunotherapy by imaging of tumor-infiltrating T cells Journal for ImmunoTherapy of Cancer |
| title | Implication of 99mTc-sum IL-2 SPECT/CT in immunotherapy by imaging of tumor-infiltrating T cells |
| title_full | Implication of 99mTc-sum IL-2 SPECT/CT in immunotherapy by imaging of tumor-infiltrating T cells |
| title_fullStr | Implication of 99mTc-sum IL-2 SPECT/CT in immunotherapy by imaging of tumor-infiltrating T cells |
| title_full_unstemmed | Implication of 99mTc-sum IL-2 SPECT/CT in immunotherapy by imaging of tumor-infiltrating T cells |
| title_short | Implication of 99mTc-sum IL-2 SPECT/CT in immunotherapy by imaging of tumor-infiltrating T cells |
| title_sort | implication of 99mtc sum il 2 spect ct in immunotherapy by imaging of tumor infiltrating t cells |
| url | https://jitc.bmj.com/content/11/3/e005925.full |
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