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 5

IACS-70654 induced an IFN-associated response and MHCI expression in 2208L tumor cells.

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IACS-70654 induced an IFN-associated response and MHCI expression in 220...
(A) Volcano plot showing –log10(P value) versus log2(fold change) in RNA expression in 2208L tumor cells treated in vivo with IACS-70654 versus those treated with vehicle. Genes demonstrating significant changes are represented by red dots. Genes associated with IFN response, antigen representation, and immunosuppression are labeled. (B) GO pathway enrichment analysis of the significantly upregulated genes in 2208L tumor cells treated in vivo with IACS-70654 versus those treated with vehicle. BP gene sets were used. The top 10 pathways are listed. (C) Violin plots showing RNA expression of representative MHCI components (B2m and H2-D1) and IFN response genes (Bst2 and Isg15) in 2208L tumor cells treated in vivo. (D) Flow cytometry analysis of MHCI expression in 2208L tumor cells treated in vivo. Left: Representative histograms of MHCI expression in 2208L tumor cells (CD45–TER119–CD31–EpCAM+). Right: MFI of MHCI in 2208L tumor cells (vehicle arm, n = 5; IACS-70654 arm, n = 6). (E) Violin plots showing RNA expression (mean ± 2 SD) of representative MHCI components B2M (meta P = –0.0373) and HLA-C (meta P = –0.006612) in human TNBC patients who did (responders) or did not (non-responders) achieve pathological complete response (pCR) after treatment of paclitaxel and pembrolizumab (anti–PD-1). Data were retrieved from published studies (50, 51). (F) Quantification of IFN-β level in 2208L tumor homogenate by cytokine/chemokine array (n = 3). For D and F, a 2-tailed, unpaired Student’s t test was used. *P < 0.05; ***P < 0.001. Data are presented as mean ± SD. For A–D and F, 2208L tumors were treated with vehicle or IACS-70654 for 7 days.