Re-purposing the pro-senescence properties of doxorubicin to introduce immunotherapy in breast cancer brain metastasis
Uceda-Castro, Rebeca; Margarido, Andreia S.; Cornet, Lesley; Vegna, Serena; Hahn, Kerstin; Song, Ji Ying; Putavet, Diana A.; van Geldorp, Mariska; Çitirikkaya, Ceren H.; de Keizer, Peter L.J.; ter Beek, Leon C.; Borst, Gerben R.; Akkari, Leila; van Tellingen, Olaf; Broekman, Marike L.D.; Vennin, Claire; van Rheenen, Jacco
(2022) Cell Reports Medicine, volume 3, issue 11, pp. 1 - 28
(Article)
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
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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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Keywords: breast cancer brain metastasis, doxorubicin, immune checkpoint blockade, mouse models, senescence, T cells, Humans, Tumor Microenvironment, Immunotherapy, Female, Doxorubicin/pharmacology, Breast Neoplasms/drug therapy, Brain Neoplasms/drug therapy, General Biochemistry,Genetics and Molecular Biology, Research Support, Non-U.S. Gov't, Journal Article
ISSN: 2666-3791
Publisher: Cell Press
Note: Funding Information: The authors thank all members of the van Rheenen laboratory for critical reading of the manuscript. The authors also thank the Pathology Department, the Animal Research facility, the Flow Cytometry facility, and the Bioimaging facility of the Netherlands Cancer Institute and Pablo Lopez-Jimenez and Dr. van Duijnen (LUMC) for technical and scientific supports. This work was supported by the European Research Council Grant CANCER-RECURRENCE 648804, the CancerGenomics.nl (Netherlands Organisation for Scientific Research) program, the Josef Steiner Cancer Research Foundation, and the Dutch Cancer Society (grant 12049) (L.A.). A.S.M. is the recipient of a fellowship from the Portuguese Foundation for Science and Technology (FCT, GABBA program-PD/BD/105748/2014). C.V. is funded by a fellowship from the Human Frontier Science Program. D.A.P. was supported by the Dutch Cancer Society (KWF) grant UMCU-7141 awarded to P.L.J.d.K. K.H. received funding from the Swiss National Science Foundation. The funders had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the paper; or in the decision to submit the paper for publication. Conceptualization: A.S.M. R.U.C. M.L.D.B. C.V. and J.v.R. Data curation, formal analysis and validation: A.S.M. C.V. L.C. S.V. R.U.C. D.A.P. M.v.G. C.C. L.t.B. Methodology and investigation: A.S.M. R.U.C. S.V. J.Y.S. K.H. P.L.J.d.K. L.t.B. G.B. L.A. O.v.T. C.V. J.v.R. Project administration and supervision: C.V. and J.v.R. Writing – original draft: A.S.M. R.U.C. C.V. and J.v.R. Writing – review and editing: J.Y.S. S.V. L.A. A.S.M. R.U.C. C.V. and J.v.R. Funding acquisition: A.S.M. C.V. J.v.R. P.L.J.d.K. is a co-founder and shareholder of Cleara Biotech BV, the Netherlands. D.A.P. works as a scientist at Cleara Biotech BV, the Netherlands. Funding Information: The authors thank all members of the van Rheenen laboratory for critical reading of the manuscript. The authors also thank the Pathology Department, the Animal Research facility, the Flow Cytometry facility, and the Bioimaging facility of the Netherlands Cancer Institute and Pablo Lopez-Jimenez and Dr. van Duijnen (LUMC) for technical and scientific supports. This work was supported by the European Research Council Grant CANCER-RECURRENCE 648804 , the CancerGenomics.nl ( Netherlands Organisation for Scientific Research ) program, the Josef Steiner Cancer Research Foundation , and the Dutch Cancer Society (grant 12049 ) (L.A.). A.S.M. is the recipient of a fellowship from the Portuguese Foundation for Science and Technology (FCT, GABBA program- PD/BD/105748/2014 ). C.V. is funded by a fellowship from the Human Frontier Science Program . D.A.P. was supported by the Dutch Cancer Society (KWF) grant UMCU-7141 awarded to P.L.J.d.K. K.H. received funding from the Swiss National Science Foundation . The funders had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the paper; or in the decision to submit the paper for publication. Publisher Copyright: © 2022 The Author(s)
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