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

Nature 2021 Sep

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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. © 2021. The Author(s), under exclusive licence to Springer Nature Limited.

Citation

Robert Bentham, Kevin Litchfield, Thomas B K Watkins, Emilia L Lim, Rachel Rosenthal, Carlos Martínez-Ruiz, Crispin T Hiley, Maise Al Bakir, Roberto Salgado, David A Moore, Mariam Jamal-Hanjani, TRACERx Consortium, Charles Swanton, Nicholas McGranahan. Using DNA sequencing data to quantify T cell fraction and therapy response. Nature. 2021 Sep;597(7877):555-560