溴尿嘧啶
三阴性乳腺癌
癌症研究
CREB结合蛋白
乳腺癌
医学
奶油
免疫
S100A8型
内科学
癌症
化学
免疫学
免疫系统
炎症
转录因子
生物化学
表观遗传学
基因
作者
Xueying Yuan,Xiaoxin Hao,Hilda L. Chan,Na Zhao,Diego A. Pedroza,Fengshuo Liu,Kang Le,Alex J. Smith,Sebastián Calderón,Nadia Lieu,Michael Soth,Philip Jones,Xiang H.-F. Zhang,Jeffrey M. Rosen
出处
期刊:PubMed
日期:2024-09-17
标识
DOI:10.1172/jci.insight.182621
摘要
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 novel and 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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