CREB-Binding Protein/P300 Bromodomain Inhibition Reduces Neutrophil Accumulation and Activates Antitumor Immunity in Triple-Negative Breast Cancer

Authors

Xueying Yuan
Xiaoxin Hao
Hilda L Chan
Na Zhao
Diego A Pedroza
Fengshuo Liu
Kang Le
Alex J Smith
Sebastian J Calderon
Nadia Lieu
Michael J Soth
Philip Jones
Xiang Hf Zhang
Jeffrey M Rosen

Publication Date

9-17-2024

Journal

JCI Insight

DOI

10.1172/jci.insight.182621

PMID

39287984

PMCID

PMC11533985

PubMedCentral® Posted Date

9-17-2024

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

yes

Keywords

Triple Negative Breast Neoplasms, Female, Humans, Animals, Neutrophils, Mice, CREB-Binding Protein, Cell Line, Tumor, Xenograft Model Antitumor Assays, E1A-Associated p300 Protein, Cell Proliferation, Antineoplastic Agents, Breast cancer, Cellular immune response, Epigenetics, Immunology, Oncology

Abstract

Tumor-associated neutrophils (TANs) have been shown to promote immunosuppression and tumor progression, and a high TAN frequency predicts poor prognosis in triple-negative breast cancer (TNBC). Dysregulation of CREB-binding protein (CBP)/P300 function has been observed with multiple cancer types. The bromodomain (BRD) of CBP/P300 has been shown to regulate its activity. In this study, we found that IACS-70654, a selective CBP/P300 BRD inhibitor, reduced TANs and inhibited the growth of neutrophil-enriched TNBC models. In the bone marrow, CBP/P300 BRD inhibition reduced the tumor-driven abnormal differentiation and proliferation of neutrophil progenitors. Inhibition of CBP/P300 BRD also stimulated the immune response by inducing an IFN response and MHCI expression in tumor cells and increasing tumor-infiltrated cytotoxic T cells. Moreover, IACS-70654 improved the response of a neutrophil-enriched TNBC model to docetaxel and immune checkpoint blockade. This provides a rationale for combining a CBP/P300 BRD inhibitor with standard-of-care therapies in future clinical trials for neutrophil-enriched TNBC.

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