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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. Patients resistant to standard-of-care chemotherapies have poor survival. EMT is a reversible process in which epithelial cells lose polarity and cell-cell junctions to gain mesenchymal traits. A hybrid EMT state that displays plasticity is correlated with chemotherapy resistance. Besides tumor intrinsic factors, tumor-associated immune cells such as neutrophils and macrophages can display a pro-tumoral phenotype and contribute to chemotherapy resistance. Epigenetic enzymes can reprogram both the tumor cell EMT and tumor-associated immune cells. Thus, targeting epigenetic enzymes is a potential strategy to improve the response of TNBC to chemotherapy. Our overall goal, therefore, is to identify novel epigenetic drug(s) that can potentially be used in the clinic in combination with chemotherapy to improve the survival of TNBC patients. Previously, we performed a morphology-based epigenetic drug screen using organoid cultures of two independent mesenchymal TNBC cell models. We identified ten epigenetic drugs able to reprogram EMT, specifically several histone deacetylase (HDAC) and bromodomain (BRD) inhibitors. We selected Quisinostat, an HDAC inhibitor, and IACS-70654, an inhibitor of p300/CBP BRD, as representative of these two classes of drugs for further study. First, we determined the effects of both inhibitors in our unique syngeneic TNBC mouse models. In a claudin-low mesenchymal model T12, IACS-70654 induced the expression of epithelial marker ZO-1, reduced tumor proliferation, and reduced the infiltration of neutrophils. Accordingly, we then treated a neutrophil-enriched luminal-like TNBC model 2208L with IACS-70654. We discovered that IACS-70654 prevented tumor growth and drastically decreased neutrophil infiltration. Quisinostat also reduced tumor proliferation, improved the response to Carboplatin, and strongly induced the expression of epithelial marker E-cadherin in the T12 model. Moreover, it reduced neutrophil and regulatory T cell infiltration significantly and increased anti-tumoral macrophage infiltration. To complement these in vivo studies, we also isolated tumor-associated macrophages from T12 and studied their response in vitro to assess the direct effects of the inhibitors. Both epigenetic drugs reduced the expression of the pro-tumoral phenotype markers Arginase 1 and CD206 and induced the expression of the anti-tumoral phenotypic markers CD86 and MHCII. In summary, we showed that both Quisinostat and IACS-70654 reduced tumor proliferation and reprogramed both tumor cell EMT and tumor-associated immune cells. Future studies will characterize the effects of both compounds in additional TNBC models and employ single-cell ATAC-seq and RNA-seq to elucidate potential mechanisms and pathways employed by these two different classes of epigenetic drugs in both tumor cells and tumor-associated immune cells. Citation Format: Xueying Yuan, Michael Soth, Philip Jones, Jeffrey Rosen. Reprogramming epithelial-mesenchymal transition and the immune microenvironment in triple-negative breast cancer with epigenetic drugs. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B020. |
