What question did this study set out to answer?

To explore the mechanisms of selective LXR modulation in myeloid cells and its impact on T cell function.

April 5, 2026Cancer Research0 citations

Abstract 5012: Multiomic profiling reveals ligand and cell specific regulatory programs of LXR selective modulation in myeloid immune cells

YFYifan Fei RKRajendra KC MFMark R. Flory

Key Points

To explore the mechanisms of selective LXR modulation in myeloid cells and its impact on T cell function.
Performed multi-omics profiling (RNA-seq, ATAC-seq, RIME proteomics) on murine bone marrow-derived macrophages and dendritic cells treated with LXR ligands.
Assessed transcriptional and chromatin accessibility patterns for shared and specific responses.
Conducted preliminary functional assays to evaluate T cell proliferation effects influenced by LXR ligands.
Identified distinct transcriptional and chromatin accessibility patterns in macrophages and dendritic cells under LXR ligand treatment.
27-hydroxycholesterol (27HC) was found to suppress specific immune signaling pathways, particularly in macrophages.
Functional assays indicated that inhibiting the E2F pathway could reverse the suppressive effects of 27HC on T cell proliferation.

Abstract

Abstract 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) are key regulators of cholesterol homeostasis, inflammation, and immune responses. LXR ligands have shown antiproliferative and immunomodulatory effects across multiple cancers, including prostate, breast, and colorectal cancers, as well as hematologic tumors. Certain LXR ligands also attenuate immunosuppressive cell populations in the tumor microenvironment, making LXR a promising therapeutic target.However, many synthetic LXR agonists have shown adverse metabolic and neurologic effects and their impact on tumor progression is often inconsistent, suggesting potential ligand- and cell-specific modulation. Understanding the mechanisms underlying such selective LXR modulation, inspired by established selective modulation strategies for ER and AR related cancers, may enable the development of safer and more effective LXR-directed cancer therapies.To elucidate the mechanism of selective LXR modulation in myeloid cells, we performed multi-omics profiling (RNA-seq, ATAC-seq, and RIME proteomics) on murine bone marrow derived macrophages and dendritic cells treated with seven LXR ligands. We observed both shared and ligand- or cell-specific transcriptional and chromatin accessibility patterns. Notably, 27-hydroxycholesterol (27HC) suppressed interferon/STAT1 programs in macrophages and induced a MYC/E2F associated immunosuppressive state, whereas dendritic cells exhibited suppression of interferon stimulated genes and MYC/E2F program.T cell proliferation can be suppressed by 27HC treated macrophages. Preliminary functional assays suggested that this effect could be reversed by inhibiting E2F pathway (CDK4/6 blockade) or by targeting NF-κB, STAT3, or HDAC2 signaling in macrophages. These findings delineate cell-specific mechanisms of LXR selective modulation and suggest that targeting LXR may fine-tune E2F, NF-κB, STAT3, and HDAC2 dependent signaling that impacting macrophage-T cell crosstalk and thereby enhance T cell antitumor function. Citation Format: Yifan Fei, Rajendra K C, Mark Flory, Natalia Julianna Krawczynska, Yu Wang, Kevin T. VanBortle, Hisham Mohammed, Erik R. Nelson. Multiomic profiling reveals ligand and cell specific regulatory programs of LXR selective modulation in myeloid immune cells abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5012.

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