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LXR/ApoE Activation Restricts Innate Immune Suppression in Cancer.
Cell ( IF 64.5 ) Pub Date : 2018-01-11 , DOI: 10.1016/j.cell.2017.12.026
Masoud F Tavazoie 1 , Ilana Pollack 1 , Raissa Tanqueco 1 , Benjamin N Ostendorf 1 , Bernardo S Reis 2 , Foster C Gonsalves 3 , Isabel Kurth 3 , Celia Andreu-Agullo 3 , Mark L Derbyshire 1 , Jessica Posada 1 , Shugaku Takeda 3 , Kimia N Tafreshian 1 , Eric Rowinsky 3 , Michael Szarek 4 , Roger J Waltzman 3 , Elizabeth A Mcmillan 1 , Connie Zhao 1 , Monica Mita 5 , Alain Mita 5 , Bartosz Chmielowski 6 , Michael A Postow 7 , Antoni Ribas 6 , Daniel Mucida 2 , Sohail F Tavazoie 1
Affiliation  

Therapeutic harnessing of adaptive immunity via checkpoint inhibition has transformed the treatment of many cancers. Despite unprecedented long-term responses, most patients do not respond to these therapies. Immunotherapy non-responders often harbor high levels of circulating myeloid-derived suppressor cells (MDSCs)-an immunosuppressive innate cell population. Through genetic and pharmacological approaches, we uncovered a pathway governing MDSC abundance in multiple cancer types. Therapeutic liver-X nuclear receptor (LXR) agonism reduced MDSC abundance in murine models and in patients treated in a first-in-human dose escalation phase 1 trial. MDSC depletion was associated with activation of cytotoxic T lymphocyte (CTL) responses in mice and patients. The LXR transcriptional target ApoE mediated these effects in mice, where LXR/ApoE activation therapy elicited robust anti-tumor responses and also enhanced T cell activation during various immune-based therapies. We implicate the LXR/ApoE axis in the regulation of innate immune suppression and as a target for enhancing the efficacy of cancer immunotherapy in patients.

中文翻译:

LXR / ApoE激活限制了癌症的固有免疫抑制。

通过检查点抑制来适应性免疫的治疗利用已改变了许多癌症的治疗方法。尽管有空前的长期反应,但大多数患者对这些疗法均无反应。免疫疗法无反应者通常具有高水平的循环骨髓源性抑制细胞(MDSCs),这是一种免疫抑制性先天细胞群。通过遗传和药理学方法,我们发现了控制多种癌症类型中MDSC丰度的途径。肝X核受体(LXR)激动性治疗可降低小鼠模型和首次在人为剂量递增的1期临床试验中治疗的患者的MDSC丰度。MDSC耗竭与小鼠和患者中细胞毒性T淋巴细胞(CTL)反应的激活有关。LXR转录靶标ApoE在小鼠中介导了这些作用,在各种基于免疫的疗法中,LXR / ApoE激活疗法可引发强大的抗肿瘤反应,并增强T细胞活化。我们将LXR / ApoE轴暗示于先天免疫抑制的调节中,并将其作为增强患者癌症免疫疗法功效的目标。
更新日期:2018-01-11
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