ORF39-05 - Multiomic Profiling Reveals Ligand and Cell-Specific Regulatory Programs of LXR Selective Modulation in Myeloid Immune Cells

Selective modulation of steroid nuclear receptors such as estrogen (ER), glucocorticoid (GR), and androgen receptors (AR) has advanced cancer therapy by enabling precise control of receptor signaling. However, selective modulation of other nuclear receptors remains underexplored. Liver X receptors (LXRs) regulate cholesterol homeostasis, inflammation, and immune responses, and LXR ligands exhibit antiproliferative and immunomodulatory effects across solid and hematologic malignancies. Certain LXR ligands also attenuate immunosuppressive cell populations in the tumor microenvironment, highlighting LXR as a potential therapeutic target.

However, many synthetic LXR agonists cause adverse metabolic or neurologic effects and show inconsistent effects on tumor progression. Moreover, endogenous oxysterols can act on myeloid cells to promote an immunosuppressive microenvironment and tumor growth, suggesting ligand- and cell-specific LXR modulation. Understanding the mechanisms underlying such selectivity may enable safer and more effective LXR-directed cancer therapies.
To elucidate the mechanism of selective LXR modulation, we performed multi-omics profiling (RNA-seq, ATAC-seq, and RIME proteomics) in murine bone marrow derived macrophages and dendritic cells treated with seven different LXR ligands. We identified both shared and ligand- or cell-specific transcriptional programs, chromatin accessibility landscapes, and LXRβ associated coregulator profiles. Notably, the endogenous oxysterol 27-hydroxycholesterol (27HC) selectively enhanced STAT3 with LXRβ and activated a MYC/E2F transcriptional program in macrophages, whereas dendritic cells showed reduced STAT3-LXRβ association and suppression of MYC/E2F activity. Guided by these observations, pharmacologic inhibition or knockdown of STAT3 partially restored T cell expansion suppressed by 27HC-treated macrophages. In parallel, integrated gene set enrichment analysis, Library of Integrated Network-based Cellular Signatures (LINCS) perturbation analysis, and ATAC-seq motif enrichment further suggested that MEK/ERK–AP1 signaling might also contributed to the 27HC induced immunosuppressive antigen presenting cell phenotype.
These findings delineate cell-specific regulatory wiring in the context of selective LXR modulation and suggest that targeting LXR may enable fine-tuning of ERK/AP-1 and STAT3 associated programs to reshape antigen-presenting cell states and enhance T cell antitumor responses. These studies lay the foundation for future personalized medicine utilizing different small molecule ligands of the LXR.