基因君官网
2016年5月31日/生物谷BIOON/–在一项新的研究中，来自日本多家研究机构的研究人员针对成人T细胞白血病/淋巴瘤病例进行测序研究，结果发现一些癌细胞中的一些增加PD-L1蛋白产生的基因变异，这些基因变异增加癌细胞抵抗免疫系统攻击。相关研究结果近期发表在Nature期刊上，论文标题为“Aberrant PD-L1 expression through 3′-UTR disruption in multiple cancers”。这些基因变异有可能作为癌症患者的识别性标志物。
之前的研究已证实癌细胞中的PD-L1蛋白表达增加会导致它们抵抗人免疫系统攻击的能力增强—T细胞表面上的PD-1受体与PD-L1结合，导致T细胞不再作出反应，从而阻止它们攻击肿瘤。在这项新的研究中，研究人员对一种特定类型的癌细胞进行基因分析以便更多地了解参与导致PD-L1表达增加的遗传过程。
研究人员对49名成人白血病或淋巴瘤患者的样品进行全基因组测序，特地寻找可能解释PD-L1表达增加的基因变异。通过这样做，他们在其中的13种样品（代表着测试的这些样品的27%）中发现诸如重复、倒位和易位之类的变异存在于第9号染色体的某一部分上，而之前的研究所发现的是负责PD-L1表达的基因组片段。他们报道这些变异似乎切掉这个蛋白编码基因的3’非编码区，而且在一些情形下，导致这个基因的开放阅读框重排，从而允许更多的PD-L1蛋白表达。
为了更深一步开展研究，研究人员随后对来自33种不同类型癌症患者的1万多份样品进行基因分析，寻找相同类型的基因变异。他们在包括8%的某些淋巴瘤患者和2%的某些类型胃癌在内的多种不同类型癌症中发现这些相同的基因变异。
研究人员接下来在模式小鼠体内利用CRISPR/Cas9进行一些基因编辑从而破坏这些基因变异带来的影响，结果发现这样做会阻止PD-L1表达增加，并且提供更多证据证实这种增加的PD-L1表达为癌细胞免受免疫攻击提供保护。（生物谷 Bioon.com）
本文系生物谷原创编译整理，欢迎转载！点击 获取授权 。更多资讯请下载生物谷APP。
Aberrant PD-L1 expression through 3′-UTR disruption in multiple cancers
Keisuke Kataoka, Yuichi Shiraishi, Yohei Takeda, Seiji Sakata, Misako Matsumoto, Seiji Nagano, Takuya Maeda, Yasunobu Nagata, Akira Kitanaka, Seiya Mizuno, Hiroko Tanaka, Kenichi Chiba, Satoshi Ito, Yosaku Watatani, Nobuyuki Kakiuchi, Hiromichi Suzuki, Tetsuichi Yoshizato, Kenichi Yoshida, Masashi Sanada, Hidehiro Itonaga, Yoshitaka Imaizumi, Yasushi Totoki, Wataru Munakata, Hiromi Nakamura, Natsuko Hama et al.
Successful treatment of many patients with advanced cancer using antibodies against programmed cell death 1 (PD-1; also known as PDCD1) and its ligand (PD-L1; also known as CD274) has highlighted the critical importance of PD-1/PD-L1-mediated immune escape in cancer development1, 2, 3, 4, 5, 6. However, the genetic basis for the immune escape has not been fully elucidated, with the exception of elevated PD-L1 expression by gene amplification and utilization of an ectopic promoter by translocation, as reported in Hodgkin and other B-cell lymphomas, as well as stomach adenocarcinoma6, 7, 8, 9, 10. Here we show a unique genetic mechanism of immune escape caused by structural variations (SVs) commonly disrupting the 3′ region of the PD-L1 gene. Widely affecting multiple common human cancer types, including adult T-cell leukaemia/lymphoma (27%), diffuse large B-cell lymphoma (8%), and stomach adenocarcinoma (2%), these SVs invariably lead to a marked elevation of aberrant PD-L1 transcripts that are stabilized by truncation of the 3′-untranslated region (UTR). Disruption of the Pd-l1 3′-UTR in mice enables immune evasion of EG7-OVA tumour cells with elevated Pd-l1 expression in vivo, which is effectively inhibited by Pd-1/Pd-l1 blockade, supporting the role of relevant SVs in clonal selection through immune evasion. Our findings not only unmask a novel regulatory mechanism of PD-L1 expression, but also suggest that PD-L1 3′-UTR disruption could serve as a genetic marker to identify cancers that actively evade anti-tumour immunity through PD-L1 overexpression.
相关会议推荐
2016（第七届）细胞治疗国际研讨会
会议时间：2016.06.17-2016.06.18 会议地点：武汉