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

• Published in: Cancer letters Vol. 465; pp. 45 - 58
• Main Authors: Andrieu, Guillaume P., Shafran, Jordan S., Smith, Charlotte L., Belkina, Anna C., Casey, Allison N., Jafari, Naser, Denis, Gerald V.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 28.11.2019; Elsevier Limited
• Subjects: Azepines - pharmacology; B7-H1 Antigen - metabolism; Bet protein; BET proteins; Breast cancer; Cell culture; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemotherapy; Clinical trials; Coculture Techniques; Cytotoxicity; Exhaustion; Female; Flow cytometry; Funding; Gene Expression Regulation, Neoplastic - drug effects; Humans; Immune exhaustion; Immune response; Immunotherapy; Interferon; Interferon-gamma - metabolism; Lymphocytes; Lymphocytes T; Metabolism; PD-1; PD-1 protein; PD-L1; PD-L1 protein; Penicillin; Programmed Cell Death 1 Receptor - metabolism; Proteins; Proteins - antagonists & inhibitors; Signal Transduction - drug effects; T-Lymphocytes - immunology; Triazoles - pharmacology; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - immunology; Triple Negative Breast Neoplasms - metabolism; Triple-negative breast cancer; γ-Interferon; PD-L1; BET proteins; PD-1; Immunotherapy; Triple-negative breast cancer; Immune exhaustion
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2019.08.013

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. •BET protein targeting suppresses PD-1/PD-L1 inhibition in triple-negative breast cancer and elicits anti-tumor immunity.•BET protein inhibition suppresses a pro-inflammatory environment prone to immune exhaustion.•BRD2, BRD3 and BRD4 are each critical for immune checkpoint expression and regulation.•Therapies for triple negative breast cancer are limited; BET protein inhibition may improve immunotherapy for these tumors.