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Using DNA sequencing data to quantify T cell fraction and therapy response
Nature ( IF 64.8 ) Pub Date : 2021-09-08 , DOI: 10.1038/s41586-021-03894-5
Robert Bentham 1, 2 , Kevin Litchfield 2, 3 , Thomas B K Watkins 4 , Emilia L Lim 2, 4 , Rachel Rosenthal 4 , Carlos Martínez-Ruiz 1, 2 , Crispin T Hiley 2, 4 , Maise Al Bakir 4 , Roberto Salgado 5, 6 , David A Moore 2, 7, 8 , Mariam Jamal-Hanjani 2, 8, 9 , , Charles Swanton 2, 4, 8 , Nicholas McGranahan 1, 2
Affiliation  

The immune microenvironment influences tumour evolution and can be both prognostic and predict response to immunotherapy1,2. However, measurements of tumour infiltrating lymphocytes (TILs) are limited by a shortage of appropriate data. Whole-exome sequencing (WES) of DNA is frequently performed to calculate tumour mutational burden and identify actionable mutations. Here we develop T cell exome TREC tool (T cell ExTRECT), a method for estimation of T cell fraction from WES samples using a signal from T cell receptor excision circle (TREC) loss during V(D)J recombination of the T cell receptor-α gene (TCRA (also known as TRA)). TCRA T cell fraction correlates with orthogonal TIL estimates and is agnostic to sample type. Blood TCRA T cell fraction is higher in females than in males and correlates with both tumour immune infiltrate and presence of bacterial sequencing reads. Tumour TCRA T cell fraction is prognostic in lung adenocarcinoma. Using a meta-analysis of tumours treated with immunotherapy, we show that tumour TCRA T cell fraction predicts immunotherapy response, providing value beyond measuring tumour mutational burden. Applying T cell ExTRECT to a multi-sample pan-cancer cohort reveals a high diversity of the degree of immune infiltration within tumours. Subclonal loss of 12q24.31–32, encompassing SPPL3, is associated with reduced TCRA T cell fraction. T cell ExTRECT provides a cost-effective technique to characterize immune infiltrate alongside somatic changes.



中文翻译:

使用 DNA 测序数据量化 T 细胞分数和治疗反应

免疫微环境影响肿瘤的进化,并且可以预测免疫治疗的反应1,2。然而,肿瘤浸润淋巴细胞(TIL)的测量由于缺乏适当的数据而受到限制。DNA 的全外显子组测序 (WES) 经常用于计算肿瘤突变负荷并识别可操作的突变。在这里,我们开发了 T 细胞外显子组 TREC 工具 (T cell ExTRECT),这是一种利用 T 细胞受体 V(D)J 重组过程中 T 细胞受体切除环 (TREC) 损失的信号来估计 WES 样本中 T 细胞分数的方法-α基因(TCRA(也称为TRA))。TCRA T 细胞分数与正交 TIL 估计值相关,且与样本类型无关。女性血液TCRA T 细胞分数高于男性,并且与肿瘤免疫浸润和细菌测序读数的存在相关。肿瘤TCRA T 细胞分数可预测肺腺癌的预后。通过对接受免疫治疗的肿瘤进行荟萃分析,我们发现肿瘤TCRA T 细胞分数可以预测免疫治疗反应,提供了超出测量肿瘤突变负荷的价值。将 T 细胞 ExTRECT 应用于多样本泛癌队列,揭示了肿瘤内免疫浸润程度的高度多样性。12q24.31-32(包括SPPL3)的亚克隆丢失与TCRA T 细胞分数减少相关。T 细胞 ExTRECT 提供了一种经济有效的技术来表征免疫浸润和体细胞变化。

更新日期:2021-09-08
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