PO.EN01.02 · 内分泌肿瘤
多组学分析揭示髓系免疫细胞中 LXR 选择性调节的配体和细胞特异性调控程序
Multiomic profiling reveals ligand and cell specific regulatory programs of LXR selective modulation in myeloid immune cells
该海报暂无可下载的资料
AACR 官方页面
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
对雌激素(ER)、糖皮质激素(GR)和雄激素受体(AR)等甾体核受体的选择性调节,通过实现对受体信号的精确控制,推动了癌症治疗的进展。然而,对其他核受体的选择性调节仍未得到充分探索。肝 X 受体(LXR)是胆固醇稳态、炎症和免疫反应的关键调控因子。LXR 配体在多种癌症中已显示出抗增殖和免疫调节作用,包括前列腺癌、乳腺癌和结直肠癌以及血液系统肿瘤。某些 LXR 配体还能减弱肿瘤微环境中的免疫抑制性细胞群,使 LXR 成为一个有前景的治疗靶点。
然而,许多合成 LXR 激动剂已显示出不良的代谢和神经系统效应,且它们对肿瘤进展的影响往往不一致,提示可能存在配体和细胞特异性的调节。借鉴针对 ER 和 AR 相关癌症已确立的选择性调节策略,理解这种选择性 LXR 调节的潜在机制,可能有助于开发更安全、更有效的 LXR 导向癌症疗法。为阐明髓系细胞中选择性 LXR 调节的机制,我们对用七种 LXR 配体处理的小鼠骨髓来源巨噬细胞和树突状细胞进行了多组学分析(RNA-seq、ATAC-seq 和 RIME 蛋白质组学)。我们观察到既有共享的、也有配体或细胞特异性的转录和染色质可及性模式。值得注意的是,27-羟基胆固醇(27HC)抑制巨噬细胞中的干扰素/STAT1 程序并诱导 MYC/E2F 相关的免疫抑制状态,而树突状细胞则表现出干扰素刺激基因和 MYC/E2F 程序的抑制。经 27HC 处理的巨噬细胞可抑制 T 细胞增殖。初步功能实验提示,该效应可通过抑制 E2F 通路(CDK4/6 阻断)或通过靶向巨噬细胞中的 NF-κB、STAT3 或 HDAC2 信号来逆转。这些发现描绘了 LXR 选择性调节的细胞特异性机制,并提示靶向 LXR 可能精细调节依赖 E2F、NF-κB、STAT3 和 HDAC2 的信号,从而影响巨噬细胞-T 细胞串扰,进而增强 T 细胞抗肿瘤功能。
查看英文原文 English 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.
利益披露 Disclosure
Y. Fei, None.