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

Humans Female Breast Neoplasms / drug therapy Brain Neoplasms / drug therapy Doxorubicin / pharmacology Immunotherapy Tumor Microenvironment
T cells breast cancer brain metastasis doxorubicin immune checkpoint blockade mouse models senescence

Journal

Cell reports. Medicine
ISSN: 2666-3791
Titre abrégé: Cell Rep Med
Pays: United States
ID NLM: 101766894

Informations de publication

Date de publication:
15 11 2022
Historique:
received: 12 11 2021
revised: 02 09 2022
accepted: 18 10 2022
entrez: 17 11 2022
pubmed: 18 11 2022
medline: 22 11 2022
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.xcrm.2022.100821 PMID: 36384097 PMC: PMC9729880
pubmed: 36384097
pii: S2666-3791(22)00380-9
doi: 10.1016/j.xcrm.2022.100821
pmc: PMC9729880
pii:
doi:

Substances chimiques

Doxorubicin 80168379AG

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

100821

Informations de copyright

Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests 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.

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Auteurs

Rebeca Uceda-Castro (R)

Division of Molecular Pathology, Oncode Institute, The Netherlands Cancer Institute, 1066 Amsterdam, North Holland, the Netherlands.

Andreia S Margarido (AS)

Division of Molecular Pathology, Oncode Institute, The Netherlands Cancer Institute, 1066 Amsterdam, North Holland, the Netherlands.

Lesley Cornet (L)

Division of Molecular Pathology, Oncode Institute, The Netherlands Cancer Institute, 1066 Amsterdam, North Holland, the Netherlands.

Serena Vegna (S)

Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, 1066 Amsterdam, North Holland, the Netherlands.

Kerstin Hahn (K)

Division of Molecular Pathology, Oncode Institute, The Netherlands Cancer Institute, 1066 Amsterdam, North Holland, the Netherlands.

Ji-Ying Song (JY)

Division of Experimental Animal Pathology, The Netherlands Cancer Institute, 1066 Amsterdam, North Holland, the Netherlands.

Diana A Putavet (DA)

Center for Molecular Medicine, Division LAB, University Medical Center Utrecht, 3584 Utrecht, North Holland, the Netherlands.

Mariska van Geldorp (M)

Division of Pharmacology, The Netherlands Cancer Institute, 1066 Amsterdam, North Holland, the Netherlands.

Ceren H Çitirikkaya (CH)

Division of Pharmacology, The Netherlands Cancer Institute, 1066 Amsterdam, North Holland, the Netherlands.

Peter L J de Keizer (PLJ)

Center for Molecular Medicine, Division LAB, University Medical Center Utrecht, 3584 Utrecht, North Holland, the Netherlands.

Leon C Ter Beek (LC)

Department of Medical Physics and Technology, The Netherlands Cancer Institute, 1066 Amsterdam, North Holland, the Netherlands.

Gerben R Borst (GR)

Department of Radiation Oncology, The Netherlands Cancer Institute, 1066 Amsterdam, North Holland, the Netherlands; Faculty of Biology, Medicine and Health, University of Manchester, Manchester M1 3WE, UK; The Christie NHS Foundation Trust, Manchester M20 4BX, UK.

Leila Akkari (L)

Division of Tumor Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, 1066 Amsterdam, North Holland, the Netherlands.

Olaf van Tellingen (O)

Division of Pharmacology, The Netherlands Cancer Institute, 1066 Amsterdam, North Holland, the Netherlands; Mouse Cancer Clinic, the Netherlands Cancer Institute, 1066 Amsterdam, North Holland, the Netherlands.

Marike L D Broekman (MLD)

Department of Neurosurgery, Leiden University Medical Center, 2300 Leiden, South-Holland, the Netherlands; Department of Neurosurgery, Haaglanden Medical Center, Lijnbaan, 2597 The Hague, South-Holland, the Netherlands; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.

Claire Vennin (C)

Division of Molecular Pathology, Oncode Institute, The Netherlands Cancer Institute, 1066 Amsterdam, North Holland, the Netherlands. Electronic address: c.vennin@nki.nl.

Jacco van Rheenen (J)

Division of Molecular Pathology, Oncode Institute, The Netherlands Cancer Institute, 1066 Amsterdam, North Holland, the Netherlands. Electronic address: j.v.rheenen@nki.nl.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Re-purposing the pro-senescence properties of...
questionsmedicales.fr › Maladies de la peau et du tissu conjonctif › Maladies de la peau › Maladies du sein › Tumeurs du sein › Re-purposing the pro-senescence properties of...
questionsmedicales.fr › Maladies du système nerveux › Tumeurs du système nerveux › Tumeurs du système nerveux central › Tumeurs du cerveau › Re-purposing the pro-senescence properties of...
questionsmedicales.fr › Glucides › Hétérosides › Aminosides › Anthracyclines › Daunorubicine › Doxorubicine › Re-purposing the pro-senescence properties of...
questionsmedicales.fr › Thérapeutique › Biothérapie › Immunothérapie › Re-purposing the pro-senescence properties of...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Microenvironnement cellulaire › Microenvironnement tumoral › Re-purposing the pro-senescence properties of...