LXR-inverse agonism stimulates immune-mediated tumor destruction by enhancing CD8 T-cell activity in triple negative breast cancer
LXR-inverse agonism stimulates immune-mediated tumor destruction by enhancing CD8 T-cell activity in triple negative breast cancer
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DOI：
10.1038/s41598-019-56038-1
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发表时间：
2019-12-20
影响因子：
4.6
通讯作者：
Flaveny, Colin A.
中科院分区：
文献类型：
--
作者：
Carpenter, Katherine J.;Valfort, Aurore-Cecile;Flaveny, Colin A.
三阴性乳腺癌（TNBC）是一种高度侵袭性的亚型，无法用激素或HER 2靶向疗法治疗，并且通常对检查点阻断免疫疗法无反应。在肿瘤微环境中，免疫细胞代谢失调已成为肿瘤免疫逃避的关键机制。我们已经发现，肝脏-X-受体（LXR α和LXR β），已知调节脂质代谢和肿瘤-免疫相互作用的核受体，在TNBC肿瘤相关骨髓细胞中高度活化。因此，我们推测抑制LXR将诱导免疫介导的TNBC-肿瘤清除。在这里，我们表明，药理学抑制LXR活性诱导肿瘤破坏主要是通过刺激CD 8 + T细胞的细胞毒活性和线粒体代谢。我们的结果表明，LXR反向激动剂可能是一类有前途的新的TNBC免疫疗法。
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 (LXR alpha and LXR beta), 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.