Journal Article

DKFZ-2025-01164

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Characterisation of an autochthonous mouse ccRCC model of immune checkpoint inhibitor therapy resistance.

Peighambari, A. ; Huang, H. ; Metzger, P. ; Adlesic, M. ; Zodel, K. ; Schäfer, S. ; Seidel, P. ; Braun, L. M. ; Hülsdünker, J. ; Melchinger, W. ; Follo, M. ; Ku, M. ; Haug, S. ; Li, Y. ; Köttgen, A. ; Schell, C. ; von Elverfeldt, D. ; Reichardt, W. ; Zeiser, R.DKFZ* ; Heikenwalder, M.DKFZ* ; Höfflin, R. ; Börries, M.DKFZ* ; Frew, I. J.DKFZ*

2025
Springer Nature [London]

This record in other databases:  

Please use a persistent id in citations: 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.

Keyword(s): Animals (MeSH) ; Immune Checkpoint Inhibitors: pharmacology (MeSH) ; Immune Checkpoint Inhibitors: therapeutic use (MeSH) ; Carcinoma, Renal Cell: drug therapy (MeSH) ; Carcinoma, Renal Cell: pathology (MeSH) ; Carcinoma, Renal Cell: immunology (MeSH) ; Carcinoma, Renal Cell: genetics (MeSH) ; Mice (MeSH) ; Kidney Neoplasms: drug therapy (MeSH) ; Kidney Neoplasms: pathology (MeSH) ; Kidney Neoplasms: immunology (MeSH) ; Kidney Neoplasms: genetics (MeSH) ; Disease Models, Animal (MeSH) ; Drug Resistance, Neoplasm (MeSH) ; Humans (MeSH) ; Tumor Microenvironment: drug effects (MeSH) ; Tumor Microenvironment: immunology (MeSH) ; CTLA-4 Antigen: antagonists & inhibitors (MeSH) ; T-Lymphocytes: immunology (MeSH) ; Programmed Cell Death 1 Receptor: antagonists & inhibitors (MeSH) ; Cell Line, Tumor (MeSH) ; Immune Checkpoint Inhibitors ; CTLA-4 Antigen ; Programmed Cell Death 1 Receptor

---

Contributing Institute(s):

1. DKTK Koordinierungsstelle Freiburg (FR01)
2. Chronische Entzündung und Krebs (D440)

Research Program(s):

1. 314 - Immunologie und Krebs (POF4-314) (POF4-314)

Appears in the scientific report 2025

---

Database coverage:
; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Physical, Chemical and Earth Sciences ; DOAJ Seal ; Ebsco Academic Search ; Essential Science Indicators ; Fees ; IF < 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

---