Abstract 2692: ELK3 is a key regulator as the response of natural killer cell therapy in triple-negative breast cancer

Abstract

Abstract Triple-negative breast cancer (TNBC) is the most challenging subtype of breast cancer because of its aggressive behavior and the limited therapeutic strategies available. In the last decade, immunotherapy has become a promising treatment to prolong survival in advanced solid cancers including TNBC. However, the efficacy of immunotherapy in solid cancers remains limited because solid tumors contain few tumor-infiltrating lymphocytes. Here, we show that targeting an ETS transcription factor ELK3 (ELK3) enhances the response of nature killer (NK) cells through intracellular and extracellular signaling. In extracellular signaling, ELK3 depletion increases CXCL16 expression level and promotes NK cell cytotoxicity through CXCL16-mediated NK cell recruitment in TNBC. In intracellular signaling, ELK3 depletion controls mitochondrial fission-fusion status to induce NK cell-mediated cell death. In silico analysis showed that ELK3 is negatively correlated with CXCL16 or MID51 expression in breast cancer patient samples. Low expression of ELK3 and high expression of CXCL16 or MID51 were associated with a better prognosis. Low expression of ELK3 and high expression of CXCL16 or MID51 were associated with increased expression of NK cell-related genes. Our findings demonstrate that ELK3-CXCL16 axis controls NK cell recruitment to target cancer cells and ELK2-MID51 axis triggers mitochondrial dysfunction-mediated apoptosis during NK cell therapy, suggesting that targeting the ELK3 gene could be an adjuvant strategy for increasing the efficacy of immunotherapy in TNBC Citation Format: Hae-Yun Jung, Yebin Lee. ELK3 is a key regulator as the response of natural killer cell therapy in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2692.