Lutetium-177 labeled iPD-L1 as a novel immunomodulator for cancer-targeted radiotherapy
Abstract Background Cancer immunotherapy is a relatively new approach to cancer treatment. Peptides that target specific pathways and cells involved in immunomodulation can potentially improve the efficacy of cancer therapy. Recently, we reported iPD-L1 as a novel inhibitor peptide that specifically...
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SpringerOpen
2025-01-01
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| Series: | EJNMMI Radiopharmacy and Chemistry |
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| Online Access: | https://doi.org/10.1186/s41181-025-00328-9 |
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| author | Myrna Luna-Gutiérrez Erika Azorín-Vega Rigoberto Oros-Pantoja Blanca Ocampo-García Pedro Cruz-Nova Nallely Jiménez-Mancilla Gerardo Bravo-Villegas Clara Santos-Cuevas Laura Meléndez-Alafort Guillermina Ferro-Flores |
| author_facet | Myrna Luna-Gutiérrez Erika Azorín-Vega Rigoberto Oros-Pantoja Blanca Ocampo-García Pedro Cruz-Nova Nallely Jiménez-Mancilla Gerardo Bravo-Villegas Clara Santos-Cuevas Laura Meléndez-Alafort Guillermina Ferro-Flores |
| author_sort | Myrna Luna-Gutiérrez |
| collection | DOAJ |
| description | Abstract Background Cancer immunotherapy is a relatively new approach to cancer treatment. Peptides that target specific pathways and cells involved in immunomodulation can potentially improve the efficacy of cancer therapy. Recently, we reported iPD-L1 as a novel inhibitor peptide that specifically targets the cancer cell ligand PD-L1 (programmed death ligand 1). PD-L1 is responsible for inhibiting the immune checkpoint protein PD-1 expressed by regulatory T cells. On the other hand, anti-PD-L1 immunotherapy in combination with external beam radiotherapy has shown improved outcomes in the treatment of breast and lung cancer. The aim of this research was to prepare 177Lu-labeled iPD-L1 and to preclinically evaluate its radiotherapeutic potential and role as a tumor immunomodulator by measuring macrophage activation, IL-10, TGFβ, and PD-L1 expression in 4T1 triple-negative breast cancer cells and murine 4T1 tumors after treatment with 177Lu-iPD-L1. Results The iPD-L1 ligand, characterized by UPLC mass, UV-Vis, and FT-IR spectroscopies, showed a chemical purity of 99%. The 177Lu-iPD-L1 radiochemical purity was 98.9 ± 1.1%. In vitro and in vivo studies demonstrated radiotracer stability in human serum (> 97% after 24 h evaluated by radio-HPLC), adequate affinity by the PDL1 protein (IC50 = 4.21 nM), and specific detection for PD-L1 assessed in 4T1, HCT116, and AR42J cancer cells, in which PD-L1 expression was verified by immunofluorescence and Western Blot assays. After treatment with 177Lu-iPD-L1 (0.4 Bq/cell), flow cytometry results showed a significant decrease in cell viability of 4T1 cells (dead 56.2%) compared to 177LuCl3 (dead 34.2%) and untreated cells (dead 9.4%). With high tumor uptake (6.97 ± 1.04%ID) and hepatobiliary and renal clearance, lutetium-177-labeled iPD-L1 delivered a tumor dose of 27 Gy/37 MBq and less than 0.36 Gy/37 MBq to non-source organs. PD-L1 positive tumors showed a significant increase in activated macrophages, PD-L1, IL-10, and TGFβ expression levels after 177Lu-iPD-L1 treatment as evaluated by ELISA assay and immunohistochemistry. Conclusions Therefore, this study warrants further dosimetric and clinical studies to determine the immunomodulatory effect and therapeutic efficacy of 177Lu-iPD-L1 in treating PD-L1-positive tumors in combination with anti-PD-1/PD-L1 immunotherapy protocols. |
| format | Article |
| id | doaj-art-b4186e76d92843f5af1a1848a54b89a3 |
| institution | Kabale University |
| issn | 2365-421X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | SpringerOpen |
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| series | EJNMMI Radiopharmacy and Chemistry |
| spelling | doaj-art-b4186e76d92843f5af1a1848a54b89a32025-01-26T12:58:26ZengSpringerOpenEJNMMI Radiopharmacy and Chemistry2365-421X2025-01-0110112310.1186/s41181-025-00328-9Lutetium-177 labeled iPD-L1 as a novel immunomodulator for cancer-targeted radiotherapyMyrna Luna-Gutiérrez0Erika Azorín-Vega1Rigoberto Oros-Pantoja2Blanca Ocampo-García3Pedro Cruz-Nova4Nallely Jiménez-Mancilla5Gerardo Bravo-Villegas6Clara Santos-Cuevas7Laura Meléndez-Alafort8Guillermina Ferro-Flores9Department of Radioactive Materials, Instituto Nacional de Investigaciones NuclearesDepartment of Radioactive Materials, Instituto Nacional de Investigaciones NuclearesFaculty of Medicine, Universidad Autónoma del Estado de MéxicoDepartment of Radioactive Materials, Instituto Nacional de Investigaciones NuclearesDepartment of Radioactive Materials, Instituto Nacional de Investigaciones NuclearesCátedras CONAHCyT, Instituto Nacional de Investigaciones NuclearesFaculty of Chemistry, Universidad Autónoma del Estado de MéxicoDepartment of Radioactive Materials, Instituto Nacional de Investigaciones NuclearesImmunology and Molecular Oncology Diagnostics Unit, Veneto Institute of Oncology IOV – IRCCSDepartment of Radioactive Materials, Instituto Nacional de Investigaciones NuclearesAbstract Background Cancer immunotherapy is a relatively new approach to cancer treatment. Peptides that target specific pathways and cells involved in immunomodulation can potentially improve the efficacy of cancer therapy. Recently, we reported iPD-L1 as a novel inhibitor peptide that specifically targets the cancer cell ligand PD-L1 (programmed death ligand 1). PD-L1 is responsible for inhibiting the immune checkpoint protein PD-1 expressed by regulatory T cells. On the other hand, anti-PD-L1 immunotherapy in combination with external beam radiotherapy has shown improved outcomes in the treatment of breast and lung cancer. The aim of this research was to prepare 177Lu-labeled iPD-L1 and to preclinically evaluate its radiotherapeutic potential and role as a tumor immunomodulator by measuring macrophage activation, IL-10, TGFβ, and PD-L1 expression in 4T1 triple-negative breast cancer cells and murine 4T1 tumors after treatment with 177Lu-iPD-L1. Results The iPD-L1 ligand, characterized by UPLC mass, UV-Vis, and FT-IR spectroscopies, showed a chemical purity of 99%. The 177Lu-iPD-L1 radiochemical purity was 98.9 ± 1.1%. In vitro and in vivo studies demonstrated radiotracer stability in human serum (> 97% after 24 h evaluated by radio-HPLC), adequate affinity by the PDL1 protein (IC50 = 4.21 nM), and specific detection for PD-L1 assessed in 4T1, HCT116, and AR42J cancer cells, in which PD-L1 expression was verified by immunofluorescence and Western Blot assays. After treatment with 177Lu-iPD-L1 (0.4 Bq/cell), flow cytometry results showed a significant decrease in cell viability of 4T1 cells (dead 56.2%) compared to 177LuCl3 (dead 34.2%) and untreated cells (dead 9.4%). With high tumor uptake (6.97 ± 1.04%ID) and hepatobiliary and renal clearance, lutetium-177-labeled iPD-L1 delivered a tumor dose of 27 Gy/37 MBq and less than 0.36 Gy/37 MBq to non-source organs. PD-L1 positive tumors showed a significant increase in activated macrophages, PD-L1, IL-10, and TGFβ expression levels after 177Lu-iPD-L1 treatment as evaluated by ELISA assay and immunohistochemistry. Conclusions Therefore, this study warrants further dosimetric and clinical studies to determine the immunomodulatory effect and therapeutic efficacy of 177Lu-iPD-L1 in treating PD-L1-positive tumors in combination with anti-PD-1/PD-L1 immunotherapy protocols.https://doi.org/10.1186/s41181-025-00328-9PD-1177Lu-labeled iPD-L1Immunotherapy177Lu targeted radiation therapy |
| spellingShingle | Myrna Luna-Gutiérrez Erika Azorín-Vega Rigoberto Oros-Pantoja Blanca Ocampo-García Pedro Cruz-Nova Nallely Jiménez-Mancilla Gerardo Bravo-Villegas Clara Santos-Cuevas Laura Meléndez-Alafort Guillermina Ferro-Flores Lutetium-177 labeled iPD-L1 as a novel immunomodulator for cancer-targeted radiotherapy EJNMMI Radiopharmacy and Chemistry PD-1 177Lu-labeled iPD-L1 Immunotherapy 177Lu targeted radiation therapy |
| title | Lutetium-177 labeled iPD-L1 as a novel immunomodulator for cancer-targeted radiotherapy |
| title_full | Lutetium-177 labeled iPD-L1 as a novel immunomodulator for cancer-targeted radiotherapy |
| title_fullStr | Lutetium-177 labeled iPD-L1 as a novel immunomodulator for cancer-targeted radiotherapy |
| title_full_unstemmed | Lutetium-177 labeled iPD-L1 as a novel immunomodulator for cancer-targeted radiotherapy |
| title_short | Lutetium-177 labeled iPD-L1 as a novel immunomodulator for cancer-targeted radiotherapy |
| title_sort | lutetium 177 labeled ipd l1 as a novel immunomodulator for cancer targeted radiotherapy |
| topic | PD-1 177Lu-labeled iPD-L1 Immunotherapy 177Lu targeted radiation therapy |
| url | https://doi.org/10.1186/s41181-025-00328-9 |
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