The Department of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USA.
The Center for Clinical Pharmacology, Saint Louis College of Pharmacy, Saint Louis, MO, 63110, USA.
Sci Rep. 2019 Dec 20;9(1):19530. doi: 10.1038/s41598-019-56038-1.
Triple-negative breast cancer (TNBC) is a highly aggressive subtype that is untreatable with hormonal or HER2-targeted therapies and is also typically unresponsive to checkpoint-blockade immunotherapy. Within the tumor microenvironment dysregulated immune cell metabolism has emerged as a key mechanism of tumor immune-evasion. We have discovered that the Liver-X-Receptors (LXRα and LXRβ), nuclear receptors known to regulate lipid metabolism and tumor-immune interaction, are highly activated in TNBC tumor associated myeloid cells. We therefore theorized that inhibiting LXR would induce immune-mediated TNBC-tumor clearance. Here we show that pharmacological inhibition of LXR activity induces tumor destruction primarily through stimulation of CD8+ T-cell cytotoxic activity and mitochondrial metabolism. Our results imply that LXR inverse agonists may be a promising new class of TNBC immunotherapies.
三阴性乳腺癌（TNBC）是一种高度侵袭性的亚型，无法通过激素或 HER2 靶向治疗，并且通常对检查点阻断免疫疗法无反应。在肿瘤微环境中，失调的免疫细胞代谢已成为肿瘤免疫逃逸的关键机制。我们发现，肝 X 受体（LXRα 和 LXRβ），一种已知调节脂质代谢和肿瘤免疫相互作用的核受体，在 TNBC 肿瘤相关髓样细胞中高度激活。因此，我们推测抑制 LXR 会诱导免疫介导的 TNBC 肿瘤清除。在这里，我们表明 LXR 活性的药理学抑制主要通过刺激 CD8+T 细胞细胞毒性活性和线粒体代谢来诱导肿瘤破坏。我们的结果表明，LXR 反向激动剂可能是一种有前途的 TNBC 免疫治疗新类别。
