Using DNA sequencing data to quantify T cell fraction and therapy response
Details
Publication Year 2021-09-23,Volume 597,Issue #7877,Page 555-560
Journal Title
Nature
Publication Type
Research article
Abstract
The immune microenvironment influences tumour evolution and can be both prognostic and predict response to immunotherapy(1,2). 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-alpha 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.
Keywords
Adenocarcinoma of Lung/diagnosis/genetics/immunology/therapy; Aspartic Acid Endopeptidases/genetics; Cohort Studies; Exome/genetics; Female; Humans; *Immunotherapy; Lymphocytes, Tumor-Infiltrating/immunology; Male; Mutation; Neoplasms/diagnosis/genetics/*immunology/*therapy; Prognosis; Receptors, Antigen, T-Cell, alpha-beta/genetics; T-Lymphocytes/*cytology/*metabolism; Exome Sequencing/economics
Department(s)
Laboratory Research
PubMed ID
34497419
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Refer to copyright notice on published article.


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