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APOE常见种系变体调节黑色素瘤进展和存活
作者:小柯机器人 发布时间:2020/5/27 15:00:41

美国洛克菲勒大学Sohail F. Tavazoie研究团队在研究中取得进展。他们的最新研究揭示人类APOE基因的常见种系变体调节黑色素瘤的进展和存活。这一研究成果发表在2020525日出版的《自然—医学》杂志上。

他们报告说,APOE4APOE2变体分别逆转了阿尔茨海默氏病效应,分别在黑色素瘤中带来了有利的结果和较差结果。相对于APOE2小鼠,表达人APOE4等位基因的小鼠表现出减少的黑色素瘤进展和转移。相对于APOE2小鼠,APOE4小鼠表现出增强的抗肿瘤免疫激活作用,T细胞耗竭实验表明,APOE基因型对黑素瘤进展的影响是由抗肿瘤免疫力的改变介导的。

一致地,与APOE2携带者相比,携带APOE4变异体的黑色素瘤患者的生存期得到了改善。值得注意的是,相对于APOE2小鼠,APOE4小鼠在PD1免疫检查点封锁下也显示出改善的预后,并且携带APOE4的患者在接受前线治疗后,抗PD1免疫疗法的生存期有所改善。

最后,通过先前证明可增强抗肿瘤免疫力的肝X受体的药理活化,来增强APOE表达,在APOE4小鼠中显示出治疗功效,而在APOE2小鼠中则没有。这些发现表明,已有的遗传学可以影响未来恶性肿瘤的进展和生存预后,并有必要对APOE基因型作为黑色素瘤结果和治疗反应的生物标志物进行前瞻性研究

据悉,APOE基因的常见种系变体是神经变性和动脉粥样硬化疾病的主要风险修饰因子,但它们对癌症预后的影响尚不清楚。

附:英文原文

Title: Common germline variants of the human APOE gene modulate melanoma progression and survival

Author: Benjamin N. Ostendorf, Jana Bilanovic, Nneoma Adaku, Kimia N. Tafreshian, Bernardo Tavora, Roger D. Vaughan, Sohail F. Tavazoie

Issue&Volume: 2020-05-25

Abstract: Common germline variants of the APOE gene are major risk modifiers of neurodegenerative and atherosclerotic diseases1,2,3, but their effect on cancer outcome is poorly defined. Here we report that, in a reversal of their effect on Alzheimer’s disease, the APOE4 and APOE2 variants confer favorable and poor outcomes in melanoma, respectively. Mice expressing the human APOE4 allele exhibited reduced melanoma progression and metastasis relative to APOE2 mice. APOE4 mice exhibited enhanced anti-tumor immune activation relative to APOE2 mice, and T cell depletion experiments showed that the effect of APOE genotype on melanoma progression was mediated by altered anti-tumor immunity. Consistently, patients with melanoma carrying the APOE4 variant experienced improved survival in comparison to carriers of APOE2. Notably, APOE4 mice also showed improved outcomes under PD1 immune checkpoint blockade relative to APOE2 mice, and patients carrying APOE4 experienced improved anti-PD1 immunotherapy survival after progression on frontline regimens. Finally, enhancing APOE expression via pharmacologic activation of liver X receptors, previously shown to boost anti-tumor immunity4, exhibited therapeutic efficacy in APOE4 mice but not in APOE2 mice. These findings demonstrate that pre-existing hereditary genetics can impact progression and survival outcomes of a future malignancy and warrant prospective investigation of APOE genotype as a biomarker for melanoma outcome and therapeutic response.

DOI: 10.1038/s41591-020-0879-3

Source: https://www.nature.com/articles/s41591-020-0879-3

期刊信息

Nature Medicine:《自然—医学》,创刊于1995年。隶属于施普林格·自然出版集团,最新IF:30.641
官方网址:https://www.nature.com/nm/
投稿链接:https://mts-nmed.nature.com/cgi-bin/main.plex