%0 Journal Article
%A Peighambari, Asin
%A Huang, Hsin
%A Metzger, Patrick
%A Adlesic, Mojca
%A Zodel, Kyra
%A Schäfer, Silvia
%A Seidel, Philipp
%A Braun, Lukas M
%A Hülsdünker, Jan
%A Melchinger, Wolfgang
%A Follo, Marie
%A Ku, Manching
%A Haug, Stefan
%A Li, Yong
%A Köttgen, Anna
%A Schell, Christoph
%A von Elverfeldt, Dominik
%A Reichardt, Wilfried
%A Zeiser, Robert
%A Heikenwalder, Mathias
%A Höfflin, Rouven
%A Börries, Melanie
%A Frew, Ian J
%T Characterisation of an autochthonous mouse ccRCC model of immune checkpoint inhibitor therapy resistance.
%J Scientific reports
%V 15
%N 1
%@ 2045-2322
%C [London]
%I Springer Nature
%M DKFZ-2025-01164
%P 19818
%D 2025
%X 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.
%K Animals
%K Immune Checkpoint Inhibitors: pharmacology
%K Immune Checkpoint Inhibitors: therapeutic use
%K Carcinoma, Renal Cell: drug therapy
%K Carcinoma, Renal Cell: pathology
%K Carcinoma, Renal Cell: immunology
%K Carcinoma, Renal Cell: genetics
%K Mice
%K Kidney Neoplasms: drug therapy
%K Kidney Neoplasms: pathology
%K Kidney Neoplasms: immunology
%K Kidney Neoplasms: genetics
%K Disease Models, Animal
%K Drug Resistance, Neoplasm
%K Humans
%K Tumor Microenvironment: drug effects
%K Tumor Microenvironment: immunology
%K CTLA-4 Antigen: antagonists & inhibitors
%K T-Lymphocytes: immunology
%K Programmed Cell Death 1 Receptor: antagonists & inhibitors
%K Cell Line, Tumor
%K Immune Checkpoint Inhibitors (NLM Chemicals)
%K CTLA-4 Antigen (NLM Chemicals)
%K Programmed Cell Death 1 Receptor (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40473819
%R 10.1038/s41598-025-04917-1
%U https://inrepo02.dkfz.de/record/301885