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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

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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 2

IACS-70654 reduced TANs and reprogrammed myeloid cells in the TIME.

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IACS-70654 reduced TANs and reprogrammed myeloid cells in the TIME.
(A) ...
(A) Flow cytometry analyses of immune cells in all TNBC models after treatment. Left: Representative contour plots of myeloid (CD45+CD11b+) populations. Middle: Quantification of TANs (T6, n = 6; all other models, n = 5). Right: Median fluorescence intensity (MFI) of Ly6G in TANs relative to the average MFI of the vehicle-treated group (T6 and PyMT-N, n = 6; 2208L and T12, n = 5). (B) Left: Representative images of S100A8 immunostaining on 2208L tumor sections. Scale bar: 50 μm. Right: Quantification of S100A8 staining (n = 12). For A and B, experiments were conducted 3 times for 2208L and twice for other models. Data from 1 representative experiment are shown. (C) Flow cytometry analysis of CD84+ TANs in 2208L tumors after treatment (n = 5). (D) MFI of H3K27ac in TANs relative to the average MFI of the vehicle-treated group in 2208L and PyMT-N tumors after treatment (2208L, n = 5; PyMT-N, n = 6). (E) Flow cytometry analyses of blood neutrophils in 2208L tumor–bearing mice after treatment and non–tumor-bearing BALB/c mice. Ordinary 1-way ANOVA and Tukey’s multiple-comparison test were used (2208L tumor–bearing mice, n = 5; non–tumor-bearing mice, n = 3). (F) UMAP plot of TAM population (monocytes included). (G) Left: Violin plot showing the expression of representative IFN-associated genes across TAM clusters. Right: Fraction of Cluster 5 in TAMs. The fraction values are labeled. (H) Flow cytometry analysis of tumor-associated mMDSCs (Ly6G–Ly6C+CD84+) in 2208L tumors after treatment (vehicle, n = 5; IACS-70654, n = 6). For A–D and H, a 2-tailed, unpaired Student’s t test was used. For A–E and H, data are presented as mean ± SD. **P < 0.01; ***P < 0.001; ****P < 0.0001. For A–H, tumors were treated with vehicle or IACS-70654 for 7 days.

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