Abstract P2-06-10: The transcription factor HLF (Hepatic Leukemia Factor) : a potential therapeutic target in triple negative breast cancer

Abstract Pivotal role of immune response in the evolution of triple negative breast cancer has been largely reported in the last decade. Our previous study highlighted the role of HLF gene as part of a four-gene signature and was found to be negatively correlated with tumoral immune cells infiltration. We investigated more precisely its implication in the immune response and TNBC tumor development. Bioinformatics analysis of publicly available TNBC patient datasets revealed that, in mesenchymal tumor subtypes expressing low levels of HLF, upregulation of genes associated with neutrophil attraction and activation pathways was observed in comparison with those expressing high HLF levels. The implication of neutrophils in cancer is contentious, as they can function either as active anti-tumoral partners or as pro-tumoral agents promoting immunosuppression and tumor growth. This ambiguity stems from their high plasticity, which enables them to switch roles during tumor progression, influenced by signals from tumoral microenvironment, in particular those from surrounding tumor cells. In this study, we employed CRISPR/Cas9 technology to inactivate the HLF gene in TNBC cell lines, enabling us to elucidate the downstream effects on the chemokine and protease inhibitor landscape that governs neutrophil infiltration and function within the microenvironment of TNBCs, especially in mesenchymal subtypes. In vivo experiments using immunodeficient mouse models revealed that HLF downregulation in TNBC mesenchymal subtypes correlates with increased neutrophil infiltration into the tumor, leading to inhibit tumor growth. Altogether, our results suggest that a reduction of HLF expression can lead in the early steps of tumor development to the awakening of the anti-tumoral function of neutrophils to enforce the necessary immunological tone to tumor elimination. Thus, HLF emerges as a potential therapeutic target in order to favor infiltration and function of anti-tumoral neutrophils to restore an efficient immune response in the aggressive mesenchymal TNBC subtype. Citation Format: Ibrahim Bouakka,Tran Dien Alicia, Sirerol, Marine, Aymeric Silvin, Rocca Anna, Fabrice Andre. The transcription factor HLF (Hepatic Leukemia Factor) : a potential therapeutic target in triple negative breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-06-10.