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Cancer Lett. 2019 Nov 28;465:45-58. doi: 10.1016/j.canlet.2019.08.013. Epub 2019 Aug 29.

BET protein targeting suppresses the PD-1/PD-L1 pathway in triple-negative breast cancer and elicits anti-tumor immune response.

Author information

1
BU-BMC Cancer Center, Boston University School of Medicine, Boston, MA, USA; Institut Necker-Enfants Malades (INEM), Institut National de Recherche Médicale (INSERM) U1151, Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Université de Paris, Paris, France. Electronic address: guillaume.andrieu@inserm.fr.
2
BU-BMC Cancer Center, Boston University School of Medicine, Boston, MA, USA.
3
Institut Necker-Enfants Malades (INEM), Institut National de Recherche Médicale (INSERM) U1151, Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Université de Paris, Paris, France.
4
Department of Pathology, Boston University School of Medicine, Boston, MA, USA; Flow Cytometry Core Facility, Boston University School of Medicine, Boston, MA, USA.
5
BU-BMC Cancer Center, Boston University School of Medicine, Boston, MA, USA. Electronic address: gdenis@bu.edu.

Abstract

Therapeutic strategies aiming to leverage anti-tumor immunity are being intensively investigated as they show promising results in cancer therapy. The PD-1/PD-L1 pathway constitutes an important target to restore functional anti-tumor immune response. Here, we report that BET protein inhibition suppresses PD-1/PD-L1 in triple-negative breast cancer. BET proteins control PD-1 expression in T cells, and PD-L1 in breast cancer cell models. BET protein targeting reduces T cell-derived interferon-γ production and signaling, thereby suppressing PD-L1 induction in breast cancer cells. Moreover, BET protein inhibition improves tumor cell-specific T cell cytotoxic function. Overall, we demonstrate that BET protein targeting represents a promising strategy to overcome tumor-reactive T cell exhaustion and improve anti-tumor immune responses, by reducing the PD-1/PD-L1 axis in triple-negative breast cancer.

KEYWORDS:

BET proteins; Immune exhaustion; Immunotherapy; PD-1; PD-L1; Triple-negative breast cancer

PMID:
31473251
PMCID:
PMC6901183
[Available on 2020-11-28]
DOI:
10.1016/j.canlet.2019.08.013

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