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 3

IACS-70654 reprogrammed BM neutrophils.

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IACS-70654 reprogrammed BM neutrophils. (A) Left: UMAP plot of BM myeloi...
(A) Left: UMAP plot of BM myeloid cells with annotations. Right: Fractions of BM myeloid cells in treated 2208L tumor–bearing and untreated non–tumor-bearing WT BALB/c mice from scRNA-seq analyses. (B) Representative flow cytometry analyses of neutrophils in the BM of treated 2208L tumor–bearing mice (7-day treatment with vehicle or IACS-70654) and untreated non–tumor-bearing WT BALB/c mice (2208L tumor–bearing mice, n = 5; non–tumor-bearing mice, n = 3). Ordinary 1-way ANOVA and Tukey’s multiple-comparison test were used. **P < 0.01; ****P < 0.0001; NS, P > 0.05. Data are presented as mean ± SD. The experiment was conducted twice. (C) Left: Pseudotime analysis of integrated BM neutrophils. The root is circled. Right: UMAP plot of BM neutrophils with annotations. (D) Fractions of pre-neutrophils and pro-neutrophils in G1, G2/M, or S cell cycle stage in the BM of 2208L tumor–bearing mice after treatment from scRNA-seq analyses. (E) Expression distribution of Il1b in integrated BM neutrophils. (F) Expression distribution of the MDSC gene signature in BM neutrophils of treated 2208L tumor–bearing mice and untreated non–tumor-bearing mice (WT). (G) Fraction of IL-1β+ neutrophils that have a high expression level (>0.55) of the MDSC gene signature in treated 2208L tumor–bearing mice and untreated non–tumor-bearing mice (WT). (H) Expression distribution of Csf3r in BM neutrophils of treated 2208L tumor–bearing mice and untreated non–tumor-bearing mice (WT). For A and C–H, 2208L tumor–bearing mice were treated with vehicle or IACS-70654 for 6 days.