BET Bromodomain Targeting Suppresses the PD-1/PD-L1 Pathway in Triple-negative Breast Cancer and Elicits Anti-tumor Immune Response

Abstract

Therapeutic strategies aiming to leverage anti-tumor immunity are being intensively investigated because they show promising results in several cancer therapies. In tumors able to evade immune clearance, the PD-1/PD-L1 pathway constitutes an important target to restore a functional antitumor 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 triplenegative breast cancer.