A detoxified TLR4 agonist inhibits tumour growth and lung metastasis of osteosarcoma by promoting CD8+ cytotoxic lymphocyte infiltration
Abstract Background Osteosarcoma is the most common malignant bone tumour with limited treatment options and poor outcomes in advanced metastatic cases. Current immunotherapies show limited efficacy, highlighting the need for novel therapeutic approaches. Systemic immune activation by Toll-like rece...
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Nature Portfolio
2025-01-01
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| Series: | BJC Reports |
| Online Access: | https://doi.org/10.1038/s44276-024-00120-3 |
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| author | Ryunosuke Oyama Akira Nabeshima Makoto Endo Alexey Novikov Toshifumi Fujiwara Capucine Phelip Nobuhiko Yokoyama Yoshinao Oda Martine Caroff Yoshihiro Matsumoto Jerome Kerzerho Yasuharu Nakashima |
| author_facet | Ryunosuke Oyama Akira Nabeshima Makoto Endo Alexey Novikov Toshifumi Fujiwara Capucine Phelip Nobuhiko Yokoyama Yoshinao Oda Martine Caroff Yoshihiro Matsumoto Jerome Kerzerho Yasuharu Nakashima |
| author_sort | Ryunosuke Oyama |
| collection | DOAJ |
| description | Abstract Background Osteosarcoma is the most common malignant bone tumour with limited treatment options and poor outcomes in advanced metastatic cases. Current immunotherapies show limited efficacy, highlighting the need for novel therapeutic approaches. Systemic immune activation by Toll-like receptor 4 (TLR4) immunostimulants has shown great promise; however, current TLR4 agonists’ toxicity hinders this systemic approach in patients with osteosarcoma. Methods We compared the antitumour effect of lipopolysaccharides (LPS) with that of an innovative chemically detoxified TLR4 agonist (Lipo-MP-LPS) in a syngeneic metastatic osteosarcoma mouse model. Lipo-MP-LPS exhibited an optimal safety and solubility profile for systemic administration at an effective dose. We evaluated tumour growth, lung metastases, and immune cell infiltration in wild-type and TLR4-mutant mice and performed selective immunodepletion. Results Lipo-MP-LPS exhibited antitumour effects against localised osteosarcoma tumours and lung metastases, like those of natural LPS. Lipo-MP-LPS promoted CD8+ T cells and M1 macrophages infiltration in primary tumours and CD8+ T cells in metastases, with an M1-phenotype macrophage shift. The Lipo-MP-LPS antitumour effects were found to depend on TLR4 and CD8+ T cells, but not on macrophages. Conclusion Lipo-MP-LPS inhibited tumour growth and lung metastasis of osteosarcoma by promoting CD8 + T cell infiltration, indicating its therapeutic potential for advanced osteosarcoma. |
| format | Article |
| id | doaj-art-09713a1080f7427abea9e813471758b0 |
| institution | Kabale University |
| issn | 2731-9377 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | BJC Reports |
| spelling | doaj-art-09713a1080f7427abea9e813471758b02025-02-02T12:11:42ZengNature PortfolioBJC Reports2731-93772025-01-013111210.1038/s44276-024-00120-3A detoxified TLR4 agonist inhibits tumour growth and lung metastasis of osteosarcoma by promoting CD8+ cytotoxic lymphocyte infiltrationRyunosuke Oyama0Akira Nabeshima1Makoto Endo2Alexey Novikov3Toshifumi Fujiwara4Capucine Phelip5Nobuhiko Yokoyama6Yoshinao Oda7Martine Caroff8Yoshihiro Matsumoto9Jerome Kerzerho10Yasuharu Nakashima11Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu UniversityHEPHAISTOS-Pharma, Université Paris-SaclayDepartment of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu UniversityHEPHAISTOS-Pharma, Université Paris-SaclayDepartment of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu UniversityHEPHAISTOS-Pharma, Université Paris-SaclayDepartment of Orthopaedic Surgery, Fukushima Medical University School of MedicineHEPHAISTOS-Pharma, Université Paris-SaclayDepartment of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu UniversityAbstract Background Osteosarcoma is the most common malignant bone tumour with limited treatment options and poor outcomes in advanced metastatic cases. Current immunotherapies show limited efficacy, highlighting the need for novel therapeutic approaches. Systemic immune activation by Toll-like receptor 4 (TLR4) immunostimulants has shown great promise; however, current TLR4 agonists’ toxicity hinders this systemic approach in patients with osteosarcoma. Methods We compared the antitumour effect of lipopolysaccharides (LPS) with that of an innovative chemically detoxified TLR4 agonist (Lipo-MP-LPS) in a syngeneic metastatic osteosarcoma mouse model. Lipo-MP-LPS exhibited an optimal safety and solubility profile for systemic administration at an effective dose. We evaluated tumour growth, lung metastases, and immune cell infiltration in wild-type and TLR4-mutant mice and performed selective immunodepletion. Results Lipo-MP-LPS exhibited antitumour effects against localised osteosarcoma tumours and lung metastases, like those of natural LPS. Lipo-MP-LPS promoted CD8+ T cells and M1 macrophages infiltration in primary tumours and CD8+ T cells in metastases, with an M1-phenotype macrophage shift. The Lipo-MP-LPS antitumour effects were found to depend on TLR4 and CD8+ T cells, but not on macrophages. Conclusion Lipo-MP-LPS inhibited tumour growth and lung metastasis of osteosarcoma by promoting CD8 + T cell infiltration, indicating its therapeutic potential for advanced osteosarcoma.https://doi.org/10.1038/s44276-024-00120-3 |
| spellingShingle | Ryunosuke Oyama Akira Nabeshima Makoto Endo Alexey Novikov Toshifumi Fujiwara Capucine Phelip Nobuhiko Yokoyama Yoshinao Oda Martine Caroff Yoshihiro Matsumoto Jerome Kerzerho Yasuharu Nakashima A detoxified TLR4 agonist inhibits tumour growth and lung metastasis of osteosarcoma by promoting CD8+ cytotoxic lymphocyte infiltration BJC Reports |
| title | A detoxified TLR4 agonist inhibits tumour growth and lung metastasis of osteosarcoma by promoting CD8+ cytotoxic lymphocyte infiltration |
| title_full | A detoxified TLR4 agonist inhibits tumour growth and lung metastasis of osteosarcoma by promoting CD8+ cytotoxic lymphocyte infiltration |
| title_fullStr | A detoxified TLR4 agonist inhibits tumour growth and lung metastasis of osteosarcoma by promoting CD8+ cytotoxic lymphocyte infiltration |
| title_full_unstemmed | A detoxified TLR4 agonist inhibits tumour growth and lung metastasis of osteosarcoma by promoting CD8+ cytotoxic lymphocyte infiltration |
| title_short | A detoxified TLR4 agonist inhibits tumour growth and lung metastasis of osteosarcoma by promoting CD8+ cytotoxic lymphocyte infiltration |
| title_sort | detoxified tlr4 agonist inhibits tumour growth and lung metastasis of osteosarcoma by promoting cd8 cytotoxic lymphocyte infiltration |
| url | https://doi.org/10.1038/s44276-024-00120-3 |
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