LXRβ/NF-κB axis alters the state of CD8+ T cells in tumours 3371

Abstract Description Liver X Receptors β (LXRβ) are pivotal transcription factors that regulate lipid metabolism in immune systems. LXRβ is known to influence the fitness and functionality of T cells; however, its impact on T cells within the tumor microenvironment remains poorly understood. Additionally, LXRβ inhibits NF-κB target genes, yet the interplay between LXRβ and NF-κB in CD8+ T cells within tumors has not been fully elucidated. This study aims to uncover the roles of LXRβ and NF-κB in modulating CD8+ T cell function in tumor microenvironments. We used CRISPR/Cas9 and retroviral transduction to modify CAR T cells, assessed their cytotoxicity in vitro, analyzed exhaustion by flow cytometry, and studied their anti-tumor effects in a mouse model. In this study, we observed changes in the expression levels of TCF1 and Ki-67 in LXRβ-engineered CAR T cells. Notably, LXRβ expression was found to regulate the secretion of cytokines IFNγ and TNFα. Furthermore, modulating NF-κB signaling altered the cytotoxic responses of both LXRβ-overexpressing (OE) and knockout (KO) CAR T cells, highlighting its potential impact on their functionality. Based on these findings, we propose that the interaction between LXRβ and NF-κB signaling plays a crucial role in modulating CAR T cell functionality. These results suggest that genetic targeting of LXRβ/NF-κB pathways could open new avenues for enhancing tumor immunotherapies. Funding Sources This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT).RS-2023-00242443) (No. RS-2023-00210035)(RS-2023-00282907) Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)