Characterisation of an autochthonous mouse ccRCC model of immune checkpoint inhibitor therapy resistance
Abstract Many metastatic clear cell renal cell carcinomas (ccRCC) are resistant to immune checkpoint inhibitor therapies, however the mechanisms underlying sensitivity or resistance remain incompletely characterised. We demonstrate that ccRCCs in the Vhl/Trp53/Rb1 mutant mouse model are resistant to...
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Nature Portfolio
2025-06-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-025-04917-1 |
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| author | Asin Peighambari Hsin Huang Patrick Metzger Mojca Adlesic Kyra Zodel Silvia Schäfer Philipp Seidel Lukas M. Braun Jan Hülsdünker Wolfgang Melchinger Marie Follo Manching Ku Stefan Haug Yong Li Anna Köttgen Christoph Schell Dominik von Elverfeldt Wilfried Reichardt Robert Zeiser Mathias Heikenwalder Rouven Höfflin Melanie Börries Ian J. Frew |
| author_facet | Asin Peighambari Hsin Huang Patrick Metzger Mojca Adlesic Kyra Zodel Silvia Schäfer Philipp Seidel Lukas M. Braun Jan Hülsdünker Wolfgang Melchinger Marie Follo Manching Ku Stefan Haug Yong Li Anna Köttgen Christoph Schell Dominik von Elverfeldt Wilfried Reichardt Robert Zeiser Mathias Heikenwalder Rouven Höfflin Melanie Börries Ian J. Frew |
| author_sort | Asin Peighambari |
| collection | DOAJ |
| description | Abstract Many metastatic clear cell renal cell carcinomas (ccRCC) are resistant to immune checkpoint inhibitor therapies, however the mechanisms underlying sensitivity or resistance remain incompletely characterised. We demonstrate that ccRCCs in the Vhl/Trp53/Rb1 mutant mouse model are resistant to combined anti-PD-1/anti-CTLA-4 therapy alone and in combination with additional therapeutic agents that reflect current ccRCC clinical trials. However, in some animals in vivo checkpoint therapy allowed isolated splenic T cells to recognise cultured ccRCC cells from the same animal, implicating the tumour microenvironment in suppression of T cell activation. We identified putative immunosuppressive myeloid cell populations with features similar to myeloid cells in the microenvironment of human ccRCC. The expression patterns of immune checkpoint ligands in both the mouse model and in human ccRCC suggests that several checkpoint systems other than PD-1 and CTLA-4 are likely to represent the dominant T cell suppressive forces in ccRCC. Our findings characterise an autochthonous mouse ccRCC model of immune checkpoint inhibitor therapy resistance and pave the way for a systematic functional dissection of the identified potential molecular barriers to effective immune therapy of ccRCC. |
| format | Article |
| id | doaj-art-0c22cc183ee540aeb2398f8e426cab70 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-0c22cc183ee540aeb2398f8e426cab702025-08-20T03:26:42ZengNature PortfolioScientific Reports2045-23222025-06-0115111710.1038/s41598-025-04917-1Characterisation of an autochthonous mouse ccRCC model of immune checkpoint inhibitor therapy resistanceAsin Peighambari0Hsin Huang1Patrick Metzger2Mojca Adlesic3Kyra Zodel4Silvia Schäfer5Philipp Seidel6Lukas M. Braun7Jan Hülsdünker8Wolfgang Melchinger9Marie Follo10Manching Ku11Stefan Haug12Yong Li13Anna Köttgen14Christoph Schell15Dominik von Elverfeldt16Wilfried Reichardt17Robert Zeiser18Mathias Heikenwalder19Rouven Höfflin20Melanie Börries21Ian J. Frew22Department of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, Medical Center - University of FreiburgDepartment of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, Medical Center - University of FreiburgInstitute of Medical Bioinformatics and Systems Medicine, Faculty of Medicine, Medical Center - University of FreiburgDepartment of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, Medical Center - University of FreiburgDepartment of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, Medical Center - University of FreiburgDepartment of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, Medical Center - University of FreiburgDepartment of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, Medical Center - University of FreiburgDepartment of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, Medical Center - University of FreiburgDepartment of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, Medical Center - University of FreiburgDepartment of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, Medical Center - University of FreiburgDepartment of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, Medical Center - University of FreiburgClinic for Pediatric Hematology & Oncology, Faculty of Medicine, Medical Center - University of FreiburgInstitute of Genetic Epidemiology, Faculty of Medicine, Medical Center - University of FreiburgInstitute of Genetic Epidemiology, Faculty of Medicine, Medical Center - University of FreiburgInstitute of Genetic Epidemiology, Faculty of Medicine, Medical Center - University of FreiburgInstitute for Surgical Pathology, Faculty of Medicine, Medical Center - University of FreiburgDivision of Medical Physics, Department of Diagnostic and Interventional Radiology, Faculty of Medicine, Medical Center - University of FreiburgDivision of Medical Physics, Department of Diagnostic and Interventional Radiology, Faculty of Medicine, Medical Center - University of FreiburgDepartment of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, Medical Center - University of FreiburgDivision of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ)Department of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, Medical Center - University of FreiburgInstitute of Medical Bioinformatics and Systems Medicine, Faculty of Medicine, Medical Center - University of FreiburgDepartment of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, Medical Center - University of FreiburgAbstract Many metastatic clear cell renal cell carcinomas (ccRCC) are resistant to immune checkpoint inhibitor therapies, however the mechanisms underlying sensitivity or resistance remain incompletely characterised. We demonstrate that ccRCCs in the Vhl/Trp53/Rb1 mutant mouse model are resistant to combined anti-PD-1/anti-CTLA-4 therapy alone and in combination with additional therapeutic agents that reflect current ccRCC clinical trials. However, in some animals in vivo checkpoint therapy allowed isolated splenic T cells to recognise cultured ccRCC cells from the same animal, implicating the tumour microenvironment in suppression of T cell activation. We identified putative immunosuppressive myeloid cell populations with features similar to myeloid cells in the microenvironment of human ccRCC. The expression patterns of immune checkpoint ligands in both the mouse model and in human ccRCC suggests that several checkpoint systems other than PD-1 and CTLA-4 are likely to represent the dominant T cell suppressive forces in ccRCC. Our findings characterise an autochthonous mouse ccRCC model of immune checkpoint inhibitor therapy resistance and pave the way for a systematic functional dissection of the identified potential molecular barriers to effective immune therapy of ccRCC.https://doi.org/10.1038/s41598-025-04917-1 |
| spellingShingle | Asin Peighambari Hsin Huang Patrick Metzger Mojca Adlesic Kyra Zodel Silvia Schäfer Philipp Seidel Lukas M. Braun Jan Hülsdünker Wolfgang Melchinger Marie Follo Manching Ku Stefan Haug Yong Li Anna Köttgen Christoph Schell Dominik von Elverfeldt Wilfried Reichardt Robert Zeiser Mathias Heikenwalder Rouven Höfflin Melanie Börries Ian J. Frew Characterisation of an autochthonous mouse ccRCC model of immune checkpoint inhibitor therapy resistance Scientific Reports |
| title | Characterisation of an autochthonous mouse ccRCC model of immune checkpoint inhibitor therapy resistance |
| title_full | Characterisation of an autochthonous mouse ccRCC model of immune checkpoint inhibitor therapy resistance |
| title_fullStr | Characterisation of an autochthonous mouse ccRCC model of immune checkpoint inhibitor therapy resistance |
| title_full_unstemmed | Characterisation of an autochthonous mouse ccRCC model of immune checkpoint inhibitor therapy resistance |
| title_short | Characterisation of an autochthonous mouse ccRCC model of immune checkpoint inhibitor therapy resistance |
| title_sort | characterisation of an autochthonous mouse ccrcc model of immune checkpoint inhibitor therapy resistance |
| url | https://doi.org/10.1038/s41598-025-04917-1 |
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