Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution.
Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution.
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DOI：
10.1016/j.cell.2017.10.001
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发表时间：
2017-11-30
期刊：
影响因子：
64.5
通讯作者：
TRACERx Consortium
中科院分区：
文献类型：
--
作者：
McGranahan N;Rosenthal R;Hiley CT;Rowan AJ;Watkins TBK;Wilson GA;Birkbak NJ;Veeriah S;Van Loo P;Herrero J;Swanton C;TRACERx Consortium
免疫逃避是癌症的标志。通过人类白细胞抗原（HLA）丧失而丧失呈递新抗原的能力可促进免疫逃避。然而，基因座的多态性本质已经排除了准确的HLA拷贝数分析。在这里，我们提出了人类白细胞抗原（LOHHLA）的杂合性丢失，这是一种从测序数据中确定HLA等位基因特异性拷贝数的计算工具。使用LOHHLA，我们发现HLA洛发生在40%的非小细胞肺癌（NSCLC）中，并与高亚克隆新抗原负荷、APOBEC介导的诱变、细胞溶解活性上调和PD-L1阳性相关。HLA洛改变的局部性质、其亚克隆频率、在转移部位的富集以及作为平行事件的发生表明HLA洛是一种免疫逃逸机制，在肿瘤进化后期受到强大的微环境选择压力。用LOHHLA表征HLA洛缺失可改善新抗原预测，并可能对我们理解耐药机制和靶向新抗原的免疫学方法有意义。LOHHLA能够从测序数据中估计等位基因特异性HLA丢失HLA基因座的洛发生在40%的早期非小细胞肺癌中HLA LOH与高亚克隆新抗原负荷和免疫活性相关HLA洛是一种受到强选择压力的免疫逃逸机制生物信息学工具LOHHLA的开发允许精确测量等位基因特异性HLA拷贝数，提高了新抗原预测的准确性，并揭示了免疫逃逸如何有助于非小细胞肺癌的肿瘤演变。
Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. LOHHLA enables estimation of allele-specific HLA loss from sequencing data LOH of the HLA locus occurs in 40% of early stage non-small-cell lung cancers HLA LOH is associated with a high subclonal neoantigen burden and immune activity HLA LOH is an immune escape mechanism subject to strong selection pressures Development of the bioinformatics tool LOHHLA allows precise measurement of allele-specific HLA copy number, improves the accuracy in neoantigen prediction, and uncovers insights into how immune escape contributes to tumor evolution in non-small-cell lung cancer.
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DOI：
10.1093/annonc/mdu479
发表时间：
2015-01
期刊：
Annals of oncology : official journal of the European Society for Medical Oncology
影响因子：
--
作者：
Favero F;Joshi T;Marquard AM;Birkbak NJ;Krzystanek M;Li Q;Szallasi Z;Eklund AC
通讯作者：
Eklund AC
抗原加工机械和HLA I类缺陷与宫颈癌中临床病理结果的关联。
影响因子：
5.8
作者：
Mehta, Akash M.;Jordanova, Ekaterina S.;Kenter, Gemma G.;Ferrone, Soldano;Fleuren, Gert-Jan
通讯作者：
Fleuren, Gert-Jan
影响因子：
7
作者：
Ha G;Roth A;Khattra J;Ho J;Yap D;Prentice LM;Melnyk N;McPherson A;Bashashati A;Laks E;Biele J;Ding J;Le A;Rosner J;Shumansky K;Marra MA;Gilks CB;Huntsman DG;McAlpine JN;Aparicio S;Shah SP
通讯作者：
Shah SP
DOI：
10.1126/science.aaf1490
发表时间：
2016-03-25
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
McGranahan N;Furness AJ;Rosenthal R;Ramskov S;Lyngaa R;Saini SK;Jamal-Hanjani M;Wilson GA;Birkbak NJ;Hiley CT;Watkins TB;Shafi S;Murugaesu N;Mitter R;Akarca AU;Linares J;Marafioti T;Henry JY;Van Allen EM;Miao D;Schilling B;Schadendorf D;Garraway LA;Makarov V;Rizvi NA;Snyder A;Hellmann MD;Merghoub T;Wolchok JD;Shukla SA;Wu CJ;Peggs KS;Chan TA;Hadrup SR;Quezada SA;Swanton C
通讯作者：
Swanton C
影响因子：
12.3
作者：
Li B;Severson E;Pignon JC;Zhao H;Li T;Novak J;Jiang P;Shen H;Aster JC;Rodig S;Signoretti S;Liu JS;Liu XS
通讯作者：
Liu XS