Using DNA sequencing data to quantify T cell fraction and therapy response

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Item Type:	Article
Title:	Using DNA sequencing data to quantify T cell fraction and therapy response
Creators Name:	Bentham, R., Litchfield, K., Watkins, T.B.K., Lim, E.L., Rosenthal, R., Martínez-Ruiz, C., Hiley, C.T., Bakir, M.A., Salgado, R., Moore, D.A., Jamal-Hanjani, M., Swanton, C. and McGranahan, N.
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.
Keywords:	Adenocarcinoma of Lung, alpha-beta T-Cell Antigen Receptors, Aspartic Acid Endopeptidases, Cohort Studies, Exome, Immunotherapy, Mutation, Neoplasms, Prognosis, T-Lymphocytes, Tumor-Infiltrating Lymphocytes, Whole Exome Sequencing
Source:	Nature
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Volume:	597
Number:	7877
Page Range:	555-560
Date:	23 September 2021
Additional Information:	Roland Schwarz, Tom L. Kaufmann and Matthew Huska are members of the TRACERx Consortium. - Copyright © The Author(s), under exclusive licence to Springer Nature Limited 2021
Official Publication:	https://doi.org/10.1038/s41586-021-03894-5
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