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

48 Pages Posted: 7 Jan 2019 Publication Status: Review Complete

See all articles by Guillaume P. Andrieu

Guillaume P. Andrieu

Boston University - Cancer Center

Jordan S. Shafran

Boston University - Cancer Center

Gerald V. Denis

Boston University - Cancer Center; Boston University - Department of Pharmacology and Experimental Therapeutics

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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.

Suggested Citation

Andrieu, Guillaume P. and Shafran, Jordan S. and Denis, Gerald V., BET Bromodomain Targeting Suppresses the PD-1/PD-L1 Pathway in Triple-negative Breast Cancer and Elicits Anti-tumor Immune Response (October 1, 2018). Available at SSRN: https://ssrn.com/abstract=3260754 or http://dx.doi.org/10.2139/ssrn.3260754
This version of the paper has not been formally peer reviewed.

Guillaume P. Andrieu (Contact Author)

Boston University - Cancer Center

One Boston Medical Center Place
Boston, MA 02118
United States

Jordan S. Shafran

Boston University - Cancer Center

One Boston Medical Center Place
Boston, MA 02118
United States

Gerald V. Denis

Boston University - Cancer Center ( email )

One Boston Medical Center Place
Boston, MA 02118
United States

Boston University - Department of Pharmacology and Experimental Therapeutics ( email )

Boston, MA 02215
United States

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