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@ARTICLE{Peighambari:301885,
author = {A. Peighambari and H. Huang and P. Metzger and M. Adlesic
and K. Zodel and S. Schäfer and P. Seidel and L. M. Braun
and J. Hülsdünker and W. Melchinger and M. Follo and M. Ku
and S. Haug and Y. Li and A. Köttgen and C. Schell and D.
von Elverfeldt and W. Reichardt and R. Zeiser$^*$ and M.
Heikenwalder$^*$ and R. Höfflin and M. Börries$^*$ and I.
J. Frew$^*$},
title = {{C}haracterisation of an autochthonous mouse cc{RCC} model
of immune checkpoint inhibitor therapy resistance.},
journal = {Scientific reports},
volume = {15},
number = {1},
issn = {2045-2322},
address = {[London]},
publisher = {Springer Nature},
reportid = {DKFZ-2025-01164},
pages = {19818},
year = {2025},
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.},
keywords = {Animals / Immune Checkpoint Inhibitors: pharmacology /
Immune Checkpoint Inhibitors: therapeutic use / Carcinoma,
Renal Cell: drug therapy / Carcinoma, Renal Cell: pathology
/ Carcinoma, Renal Cell: immunology / Carcinoma, Renal Cell:
genetics / Mice / Kidney Neoplasms: drug therapy / Kidney
Neoplasms: pathology / Kidney Neoplasms: immunology / Kidney
Neoplasms: genetics / Disease Models, Animal / Drug
Resistance, Neoplasm / Humans / Tumor Microenvironment: drug
effects / Tumor Microenvironment: immunology / CTLA-4
Antigen: antagonists $\&$ inhibitors / T-Lymphocytes:
immunology / Programmed Cell Death 1 Receptor: antagonists
$\&$ inhibitors / Cell Line, Tumor / Immune Checkpoint
Inhibitors (NLM Chemicals) / CTLA-4 Antigen (NLM Chemicals)
/ Programmed Cell Death 1 Receptor (NLM Chemicals)},
cin = {FR01 / D440},
ddc = {600},
cid = {I:(DE-He78)FR01-20160331 / I:(DE-He78)D440-20160331},
pnm = {314 - Immunologie und Krebs (POF4-314)},
pid = {G:(DE-HGF)POF4-314},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:40473819},
doi = {10.1038/s41598-025-04917-1},
url = {https://inrepo02.dkfz.de/record/301885},
}