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 4

IACS-70654 reprogrammed abnormal myelopoiesis induced by the neutrophil-enriched tumor.

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IACS-70654 reprogrammed abnormal myelopoiesis induced by the neutrophil-...
(A) UMAP plot with annotations (left) and pseudotime analysis (right) of integrated HSPC clusters. (B) Fraction of myeloid progenitor cells in HSPCs of treated 2208L tumor–bearing mice and untreated non–tumor-bearing WT mice. (C) Expression distribution of neutrophil differentiation signature from scRNA-seq analyses of HSPCs in treated 2208L tumor–bearing mice and untreated non–tumor-bearing WT mice. (D) GO pathway enrichment analysis of the significantly downregulated genes in cluster 4 (annotated as CMP-1) of HSPCs of 2208L tumor–bearing mice treated with IACS-70654 versus vehicle. Biological Process (BP) gene sets from the GO database were used. The top 8 pathways are listed. (E) Violin plots showing the RNA expression of Prtn3 in CMP-1 and MPPs of treated 2208L tumor–bearing mice and untreated non–tumor-bearing WT mice. (F) Violin plot showing the RNA expression of Ms4a3 in CMP-1 of treated 2208L tumor–bearing mice and untreated non–tumor-bearing WT mice. (G) Violin plots showing the RNA expression of Malat1 in CMP-1, MPPs, and HSCs from treated 2208L tumor–bearing mice and untreated non–tumor-bearing WT mice. For A–G, 2208L tumor–bearing mice were treated with vehicle or IACS-70654 for 6 days.