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

Bentham, Robert ; Litchfield, Kevin ; Watkins, Thomas B K ; Lim, Emilia L ; Rosenthal, Rachel ; Martínez-Ruiz, Carlos ; Hiley, Crispin T ; Bakir, Maise Al ; Salgado, Roberto ; Moore, David A ; Jamal-Hanjani, Mariam ; Swanton, Charles ; McGranahan, Nicholas

Nature (London), 2021-09, Vol.597 (7877), p.555-560 [Periódico revisado por pares]

England: Nature Publishing Group

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Título:
Using DNA sequencing data to quantify T cell fraction and therapy response
Autor: Bentham, Robert ; Litchfield, Kevin ; Watkins, Thomas B K ; Lim, Emilia L ; Rosenthal, Rachel ; Martínez-Ruiz, Carlos ; Hiley, Crispin T ; Bakir, Maise Al ; Salgado, Roberto ; Moore, David A ; Jamal-Hanjani, Mariam ; Swanton, Charles ; McGranahan, Nicholas
Assuntos: Adenocarcinoma ; Adenocarcinoma of Lung - diagnosis ; Adenocarcinoma of Lung - genetics ; Adenocarcinoma of Lung - immunology ; Adenocarcinoma of Lung - therapy ; Aspartic Acid Endopeptidases - genetics ; Cancer ; Cellular therapy ; Cohort Studies ; DNA sequencing ; Exome - genetics ; Exome Sequencing - economics ; Female ; Genetic aspects ; Histopathology ; Humans ; Immunotherapy ; Lung cancer ; Lymphocytes ; Lymphocytes T ; Lymphocytes, Tumor-Infiltrating - immunology ; Lymphoma ; Male ; Metastases ; Methods ; Microenvironments ; Mutation ; Neoplasms - diagnosis ; Neoplasms - genetics ; Neoplasms - immunology ; Neoplasms - therapy ; Nucleotide sequencing ; Physiological aspects ; Prognosis ; Receptors ; Receptors, Antigen, T-Cell, alpha-beta - genetics ; Sex differences ; Systematic review ; T cell receptors ; T cells ; T-Lymphocytes - cytology ; T-Lymphocytes - metabolism ; Tumors ; V(D)J recombination
É parte de: Nature (London), 2021-09, Vol.597 (7877), p.555-560
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Descrição: 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.
Editor: England: Nature Publishing Group
Idioma: Inglês

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

Bentham, Robert ; Litchfield, Kevin ; Watkins, Thomas B K ; Lim, Emilia L ; Rosenthal, Rachel ; Martínez-Ruiz, Carlos ; Hiley, Crispin T ; Bakir, Maise Al ; Salgado, Roberto ; Moore, David A ; Jamal-Hanjani, Mariam ; Swanton, Charles ; McGranahan, Nicholas

England: Nature Publishing Group

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