CREB-binding protein/P300 bromodomain inhibition reduces neutrophil accumulation and activates antitumor immunity in triple-negative breast cancer
Xueying Yuan, … , Xiang H.F. Zhang, Jeffrey M. Rosen
Xueying Yuan, … , Xiang H.F. Zhang, Jeffrey M. Rosen
Published September 17, 2024
Citation Information: JCI Insight. 2024;9(20):e182621. https://doi.org/10.1172/jci.insight.182621.
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Research Article Immunology Oncology

CREB-binding protein/P300 bromodomain inhibition reduces neutrophil accumulation and activates antitumor immunity in triple-negative breast cancer

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.

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 H.F. Zhang, Jeffrey M. Rosen

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Figure 1

IACS-70654 suppressed the growth of neutrophil-enriched preclinical mouse models of TNBC.

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IACS-70654 suppressed the growth of neutrophil-enriched preclinical mous...
(A) Representative images of H&E and immunostaining of all TNBC preclinical mouse models used. F4/80 is a macrophage marker, and S100A8 is a neutrophil marker. Scale bars: 50 μm. (B) Flow cytometry analysis of TANs and TAMs in all TNBC preclinical mouse models used (T6, n = 6; all other models, n = 5). (C) The treatment scheme of IACS-70654 in a 7-day experiment. When the average tumor volume reached 80–250 mm3, the mice were randomized to initiate treatment. Vehicle or IACS-70654 at 3.75 mg/kg was administered orally on a 3-on/2-off schedule. On day 7, mice were euthanized 2 hours after receiving the last treatment. (D) Tumor growth curves of all TNBC models treated with IACS-70654 for 7 days (2208L, n = 6; all other models, n = 5). Two-way ANOVA and Šidák’s multiple-comparison test were used. (E) Left: Representative images of immunostaining of BrdU in 2208L tumor sections treated with vehicle or IACS-70654 for 7 days. Scale bar: 50 μm. Right: Quantification of BrdU staining (n = 15). A 2-tailed, unpaired Student’s t test was used. For B, D, and E, data are presented as mean ± SD. *P < 0.05; ****P < 0.0001. The experiments were conducted 3 times for 2208L and twice for other models. Data from 1 representative experiment are shown. (F) Tumor growth curves (from 1 representative experiment) of 2208L tumors treated with IACS-70654 for 27 days. The experiment was conducted twice.