2. Academic Validation
  3. Characterisation of an autochthonous mouse ccRCC model of immune checkpoint inhibitor therapy resistance

Characterisation of an autochthonous mouse ccRCC model of immune checkpoint inhibitor therapy resistance

  • Sci Rep. 2025 Jun 5;15(1):19818. doi: 10.1038/s41598-025-04917-1.
Asin Peighambari 1,  Hsin Huang 1,  Patrick Metzger 2,  Mojca Adlesic 1,  Kyra Zodel 1,  Silvia Schäfer 1,  Philipp Seidel 1,  Lukas M Braun 1,  Jan Hülsdünker 1,  Wolfgang Melchinger 1,  Marie Follo 1,  Manching Ku 3,  Stefan Haug 4,  Yong Li 4,  Anna Köttgen 4,  Christoph Schell 5,  Dominik von Elverfeldt 6,  Wilfried Reichardt 6,  Robert Zeiser 1 7 8,  Mathias Heikenwalder 9,  Rouven Höfflin 1,  Melanie Börries 2 7 8,  Ian J Frew 10 11 12 13
Affiliations

Affiliations

  • 1 Department of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany.
  • 2 Institute of Medical Bioinformatics and Systems Medicine, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany.
  • 3 Clinic for Pediatric Hematology & Oncology, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany.
  • 4 Institute of Genetic Epidemiology, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany.
  • 5 Institute for Surgical Pathology, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany.
  • 6 Division of Medical Physics, Department of Diagnostic and Interventional Radiology, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany.
  • 7 Comprehensive Cancer Center Freiburg (CCCF), Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany.
  • 8 Partner Site Freiburg, German Cancer Consortium (DKTK), Freiburg, Germany.
  • 9 Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 10 Department of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany. [email protected].
  • 11 Comprehensive Cancer Center Freiburg (CCCF), Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany. [email protected].
  • 12 Partner Site Freiburg, German Cancer Consortium (DKTK), Freiburg, Germany. [email protected].
  • 13 Signalling Research Centre BIOSS, University of Freiburg, Freiburg, Germany. [email protected].
PMID: 40473819 DOI: 10.1038/s41598-025-04917-1
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.

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