Re-purposing the pro-senescence properties of doxorubicin to introduce immunotherapy in breast cancer brain metastasis
Margarido, A. S.
Song, J. Y.
Putavet, D. A.
van Geldorp, M.
Çitirikkaya, C. H.
de Keizer, P. L. J.
Ter Beek, L. C.
Borst, Gerben R
van Tellingen, O.
Broekman, M. L. D.
van Rheenen, J.
AffiliationDivision of Molecular Pathology, Oncode Institute, The Netherlands Cancer Institute, 1066 Amsterdam, North Holland, the Netherlands
MetadataShow full item record
AbstractAn increasing number of breast cancer patients develop brain metastases (BM). Standard-of-care treatments are largely inefficient, and breast cancer brain metastasis (BCBM) patients are considered untreatable. Immunotherapies are not successfully employed in BCBM, in part because breast cancer is a "cold" tumor and also because the brain tissue has a unique immune landscape. Here, we generate and characterize immunocompetent models of BCBM derived from PyMT and Neu mammary tumors to test how harnessing the pro-senescence properties of doxorubicin can be used to prime the specific immune BCBM microenvironment. We reveal that BCBM senescent cells, induced by doxorubicin, trigger the recruitment of PD1-expressing T cells to the brain. Importantly, we demonstrate that induction of senescence with doxorubicin improves the efficacy of immunotherapy with anti-PD1 in BCBM in a CD8 T cell-dependent manner, thereby providing an optimized strategy to introduce immune-based treatments in this lethal disease. In addition, our BCBM models can be used for pre-clinical testing of other therapeutic strategies in the future.
CitationUceda-Castro R, Margarido AS, Cornet L, Vegna S, Hahn K, Song JY, et al. Re-purposing the pro-senescence properties of doxorubicin to introduce immunotherapy in breast cancer brain metastasis. Cell reports Medicine. 2022 Nov 15;3(11):100821. PubMed PMID: 36384097. Pubmed Central PMCID: PMC9729880. Epub 2022/11/18. eng.
JournalCell Reports. Medicine
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- Issue date: 2019 Jul
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