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肺癌演变中的异位基因特异性HLA损失和免疫逃逸

Nicholas McGranahan¹, Rachel Rosenthal¹, Crispin T Hiley²

¹Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK.

|November 7, 2017

概括

人类白细胞抗原 (HLA) 损失是癌症常见的免疫规避策略. 一种名为LOHHLA的新工具揭示了40%的非小细胞肺癌的HLA损失,影响了新抗原预测和免疫治疗.

科学领域:

癌症学
免疫学
遗传学

背景情况:

免疫系统的逃避是癌症发展的关键标志.
人类白细胞抗原 (HLA) 表达的丧失可以通过阻碍新抗原呈现来促进癌症免疫逃避.
HLA位点的高多态性使准确的副本数分析变得复杂.

研究的目的:

介绍LOHHLA,一种用于从测序数据中确定HLA等位基因特异拷贝数的新计算工具.
在非小细胞肺癌 (NSCLC) 中研究HLA异构性丧失的频率和特征.
探索HLA-LOH与瘤突变格局,免疫活动和临床特征的关联.

主要方法:

开发LOHHLA,一种利用测序数据来评估HLA等位基因特异拷贝数的计算工具.
用LOHHLA分析非小细胞肺癌队列中的HLA拷贝数变化.
确定HLA-LOH事件与基因组/转录组特征之间的相关性分析,包括新抗原负荷,APOBEC突变和PD-L1表达.

主要成果:

在分析的非小细胞肺癌中,检测到40%的HLA- LOH.
HLA- LOH与亚克隆新抗原负荷增加,APOBEC介导的突变和PD- L1阳性显著相关.
焦点性质,亚克隆频率和转移部位的丰富表明HLA-LOH在选择压力下作为晚期进化的免疫逃生机制.

结论:

LOHHLA提供了一种强大的方法来表征HLA拷贝数的变化.
HLA-LOH是NSCLC中常见且重要的免疫逃生机制,影响瘤免疫微环境.
使用LOHHLA对HLALOH进行表征可以完善新抗原预测,并为癌症免疫治疗策略提供信息.

关键词:

生物信息学癌症的演变染色体不稳定性副本编号不同质性免疫编辑免疫逃生失去了异性肺癌肺癌新抗原

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