期刊
NATURE COMMUNICATIONS
卷 11, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-020-17644-0
关键词
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资金
- Fondation pour la Recherche Medicale [FRM FDT201904008383]
- Foundation Philanthropia
- German Cancer Aid [70113311, 34102524]
- Ligue contre le Cancer (equipe labellisee)
- Agence National de la Recherche (ANR) -Projets blancs
- ANR
- Association pour la recherche sur le cancer (ARC)
- Canceropole Ile-de-France
- Chancelerie des universites de Paris (Legs Poix)
- Fondation pour la Recherche Medicale (FRM)
- European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR)
- Gustave Roussy Odyssea, the European Union Horizon 2020 Project Oncobiome
- Fondation Carrefour
- High-end Foreign Expert Program in China, Institut National du Cancer (INCa) [GDW20171100085, GDW20181100051]
- Inserm (HTE)
- Institut Universitaire de France
- LeDucq Foundation
- LabEx Immuno-Oncology
- RHU Torino Lumiere
- Seerave Foundation
- SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE)
- SIRIC Cancer Research and Personalized Medicine (CARPEM)
- Breakthrough Level 2 grant from the US Department of Defense (DoD), Breast Cancer Research Program (BRCP) [BC180476P1]
- 2019 Laura Ziskin Prize in Translational Research from the Stand Up to Cancer (SU2C) [ZP-6177]
- Mantle Cell Lymphoma Research Initiative (MCL-RI) grant from the Leukemia and Lymphoma Society (LLS)
- Dept. of Radiation Oncology at Weill Cornell Medicine (New York, US)
- Rapid Response Grant from the Functional Genomics Initiative (New York, US)
- Lytix (Oslo, Norway)
- Phosplatin (New York, US)
Hormone receptor (HR)(+) breast cancer (BC) causes most BC-related deaths, calling for improved therapeutic approaches. Despite expectations, immune checkpoint blockers (ICBs) are poorly active in patients with HR+ BC, in part reflecting the lack of preclinical models that recapitulate disease progression in immunocompetent hosts. We demonstrate that mammary tumors driven by medroxyprogesterone acetate (M) and 7,12-dimethylbenz[a]anthracene (D) recapitulate several key features of human luminal B HR(+)HER2(-) BC, including limited immune infiltration and poor sensitivity to ICBs. M/D-driven oncogenesis is accelerated by immune defects, demonstrating that M/D-driven tumors are under immunosurveillance. Safe nutritional measures including nicotinamide (NAM) supplementation efficiently delay M/D-driven oncogenesis by reactivating immunosurveillance. NAM also mediates immunotherapeutic effects against established M/D-driven and transplantable BC, largely reflecting increased type I interferon secretion by malignant cells and direct stimulation of immune effector cells. Our findings identify NAM as a potential strategy for the prevention and treatment of HR+ BC. Current preclinical models to investigate human HR+breast cancer progression and response to immunotherapy in vivo are limited. Here, the authors demonstrate that mammary tumours driven by a synthetic progestin combined with an oral carcinogen recapitulate several immunobiological features of human HR+breast cancers.
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