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    Re-purposing the pro-senescence properties of doxorubicin to introduce immunotherapy in breast cancer brain metastasis

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    Authors
    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.
    Ter Beek, L. C.
    Borst, Gerben R
    Akkari, L.
    van Tellingen, O.
    Broekman, M. L. D.
    Vennin, C.
    van Rheenen, J.
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    Affiliation
    Division of Molecular Pathology, Oncode Institute, The Netherlands Cancer Institute, 1066 Amsterdam, North Holland, the Netherlands
    Issue Date
    2022
    
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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.
    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.
    Journal
    Cell Reports. Medicine
    URI
    http://hdl.handle.net/10541/625852
    DOI
    10.1016/j.xcrm.2022.100821
    PubMed ID
    36384097
    Additional Links
    https://dx.doi.org/10.1016/j.xcrm.2022.100821
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.xcrm.2022.100821
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