笑对人生 (2023-06-30 21:33):
#paper doi: 10.1038/s41586-021-03894-5. Epub 2021 Sep 8. Bentham R, et al. Using DNA sequencing data to quantify T cell fraction and therapy response. Nature. 2021 Sep;597(7877):555-560. doi: 10.1038/s41586-021-03894-5. Epub 2021 Sep 8. 在V(D)J重排过程中,T细胞受体alpha链编码基因(TCRA或TRA,T cell receptor-alpha gene)通常会发生丢失(TREC,T cell receptor excision circle)。基于此,本研究针对肿瘤配对的全外显子组测序数据开发了一个名为T cell ExTRECT的T细胞比例估计工具。该工具的原理主要是通过检测TRA基因发生肿瘤体细胞拷贝数变化(RDR,read-depth ratio),进而直接定量T细胞的比例。局限性:不能区分发生新抗原反应的T细胞和检测克隆型(clonotype);只能应用于全外显子组测序,要求测序深度大于30x。
IF:50.500Q1 Nature, 2021-09. DOI: 10.1038/s41586-021-03894-5 PMID: 34497419
Using DNA sequencing data to quantify T cell fraction and therapy response
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Abstract:
The immune microenvironment influences tumour evolution and can be both prognostic and predict response to immunotherapy. 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.
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