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Re-purposing the pro-senescence properties of doxorubicin to introduce immunotherapy in breast cancer brain metastasis
Uceda-Castro, R. Margarido, A. S. Cornet, L. Vegna, S. Hahn, K. Song, J. Y. Putavet, D. A. van Geldorp, M. Çitirikkaya, C. H. de Keizer, P. L. J.
Uceda-Castro, R.
Margarido, A. S.
Cornet, L.
Vegna, S.
Hahn, K.
Song, J. Y.
Putavet, D. A.
van Geldorp, M.
Çitirikkaya, C. H.
de Keizer, P. L. J.
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Abstract
An 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.
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Date
2022
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Article
Citation
Uceda-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.