CBP/P300 BRD Inhibition Reduces Neutrophil Accumulation and Activates Antitumor Immunity in TNBC

Yuan, X.; Hao, X.; Chan, H. L.; Zhao, N.; Pedroza, D. A.; Liu, F.; Le, K.; Smith, A. J.; Calderon, S. J.; Lieu, N.; Soth, M. J.; Jones, P.; Zhang, X. H.- F.; Rosen, J. M.

doi:10.1101/2024.04.25.590983

bioRxiv · 10.1101/2024.04.25.590983

CBP/P300 BRD Inhibition Reduces Neutrophil Accumulation and Activates Antitumor Immunity in TNBC

Yuan, X.·Hao, X.·Chan, H. L.·Zhao, N.·Pedroza, D. A.·Liu, F.·Le, K.·Smith, A. J.·Calderon, S. J.·Lieu, N.·Soth, M. J.·Jones, P.·Zhang, X. H.- F.·Rosen, J. M.

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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 novel and 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 CTLs. 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. SummaryIn neutrophil-enriched triple-negative breast cancer (TNBC) models, CREB binding protein (CBP)/P300 bromodomain (BRD) inhibition reduces tumor growth and systemic neutrophil accumulation while stimulating an antitumor immune response. This improves standard-of-care therapies, suggesting a potential therapeutic benefit of CBP/P300 BRD inhibitors for neutrophil-enriched TNBC.

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Yuan, X., Hao, X., Chan, H. L., Zhao, N., Pedroza, D. A., Liu, F., Le, K., Smith, A. J., Calderon, S. J., Lieu, N., Soth, M. J., Jones, P., Zhang, X. H.- F., Rosen, J. M.. 2024-04-27. CBP/P300 BRD Inhibition Reduces Neutrophil Accumulation and Activates Antitumor Immunity in TNBC. https://doi.org/10.1101/2024.04.25.590983

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