Abstract B047: Epigenetic reprogramming by CBP/P300 bromodomain inhibition of triple-negative breast cancer and the immune microenvironment
Authors: Yuan Xueying , Soth Michael , Zhao Na , Jones Philip , Rosen Jeffrey 
Published: February 2024

Abstract
Triple-negative breast cancer (TNBC) is a biologically heterogeneous and clinically important breast cancer subtype because if considered a distinct disease, TNBC would rank as the 5th leading cause of cancer deaths in women. TNBC patients resistant to standard-of-care therapies have poor survival. Tumor-associated immune cells such as neutrophils and macrophages can display a pro-tumoral phenotype and contribute to therapy resistance. Epigenetic enzymes have been shown to reprogram both the tumor cells and tumor-associated immune cells. Thus, targeting epigenetic enzymes is a potential strategy to improve the response of TNBC to standard-of-care therapies. Previously, our laboratory performed an epigenetic drug screen and identified several epigenetic inhibitors. We selected IACS-70654, a novel selective p300/CBP BRD inhibitor, to be the primary focus of this study. We determined the effects of IACS-70654 in our unique syngeneic TNBC mouse models. In a neutrophil-enriched luminal-like TNBC model 2208L, IACS-70654 as a single agent initially caused tumor regression and then durably prevented tumor growth, which is not usually observed for single agents in these aggressive TNBC models. IACS-70654 also substantially decreased infiltrated neutrophils. In the peripheral blood and bone marrow of 2208L tumor-bearing mice, IACS-70654 reduced neutrophils to the same level as non-tumor-bearing mice. Based on this finding, we treated 2208L tumors with IACS-70654 in combination with immune checkpoint blockade anti-PD1 and docetaxel. After 27 days, all treatments besides anti-PD1 were stopped, and the combination-treated tumors grew slower than the ones only treated with IACS-70654. More importantly, in tumors treated with IACS-70654 in combination with anti-PD1, there was a substantial increase in CD8+ T cell infiltration. In addition, B cell infiltration was induced in the tumor stroma, indicating that IACS-70654 stimulated immune response in the tumor microenvironment. In contrast, IACS-70654 failed to significantly reduce the growth of T12, a Claudin-low macrophage-enriched model. Therefore, we hypothesized that the infiltrated immune profiles, specifically myeloid cell infiltration, might partially account for this differential response. Accordingly, we studied the effects of IACS-70654 in two additional models, basal-like T6 and luminal-like 2250L tumors, which also have relatively high neutrophil infiltration. However, one of the principal differences in immune profiles between the two models and 2208L is that they also are infiltrated with twice as many macrophages. The response of infiltrated immune cells to IACS-70654 in those two models differed from those of 2208L tumors. IACS-70654 reduced monocytic myeloid-derived suppressor cells and pro-tumor macrophages. These results illustrate the immune heterogeneity among our tumor models. We are currently performing ChIP-seq and single-cell ATAC-seq to elucidate potential mechanisms and pathways employed by IACS-70654 in both tumor and tumor-associated immune cells.
Citation Format: Xueying Yuan, Michael Soth, Na Zhao, Philip Jones, Jeffrey Rosen. Epigenetic reprogramming by CBP/P300 bromodomain inhibition of triple-negative breast cancer and the immune microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B047.