Using DNA sequencing data to quantify T cell fraction and therapy response
- Author(s)
- Bentham, R; Litchfield, K; Watkins, TBK; Lim, EL; Rosenthal, R; Martinez-Ruiz, C; Hiley, CT; Al Bakir, M; Salgado, R; Moore, DA; Jamal-Hanjani, M; TRACERx Consortium; Swanton, C; McGranahan, N;
- 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
- Publisher's Version
- https://doi.org/10.1038/s41586-021-03894-5
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2025-06-06 07:51:41
Last Modified: 2025-06-06 07:57:04