Abstract PD5-07: PD5-07 Hepatic Leukemia Factor (HLF), a potential therapeutic target in triple negative breast cancer

Abstract The importance of the antitumor immune response in triple negative breast cancer (TNBC) is well established. We showed previously that the extent of tumor-infiltrating lymphocytes (TILs) in the residual disease after neoadjuvant chemotherapy is associated with a better prognosis. By analyzing 99 pretreatment samples we discovered that the expression of the transcription factor Hepatic Leukemia Factor (HLF) in tumor cells is associated with lower infiltration of immune cells, leading to bad prognosis. Thereby, the aim of our project is to investigate the cellular and molecular mechanism regulated by HLF to better understand the tumor immune microenvironment, so we can develop better treatment options for patients with TNBC. Analysis of publicly available datasets of TNBC (METABRIC and TCGA) showed that tumors with low levels of HLF correlate with the upregulation of genes involved in biological processes associated with the regulation of immune response and in particular with neutrophils activation. Analysis of HLF expression patterns in these patients indicate that tumors presenting a mesenchymal profile exhibited higher HLF levels than the other TNBC subtypes. To elucidate the mechanism of this phenomenon regulated by HLF and his implication in anti-tumoral immune response, we developed several human TNBC cell lines knock-out or knock-down for our target gene using CRISPR/Cas9 editing technology. Comparison of the transcriptomes showed that the silencing of HLF in some mesenchymal TNBC cell lines lead to the upregulation of components involved in the attraction and activation of neutrophils, including CXCL8 (Neutrophil-activating peptide 1), a major cytokine directly responsible for the attraction of neutrophils in the tumor site. In vitro migration experiments supported these observations since purified blood circulating neutrophils have defective migration capacity that depends on the presence or absence of HLF. Finally, the co-culture of neutrophils with tumor cells silenced for HLF showed us, using a large panel of antibodies by spectral flow cytometry, an activated state of mature neutrophils. In conclusion, our study suggest that HLF plays a fundamental role in the regulation of genes involved in the control of tumoral immune microenvironment through the attraction and the activation of mature neutrophils. These findings have the potential for important implications since they suggest that HLF can be a potential target in treating TNBC. Citation Format: Ibrahim BOUAKKA, Alicia TRAN-DIEN, Marine SIREROL, Aymeric Silvin, Fabrice Andre, Anna ROCCA. PD5-07 Hepatic Leukemia Factor (HLF), a potential therapeutic target in triple negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD5-07.