期刊
NATURE
卷 597, 期 7877, 页码 555-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41586-021-03894-5
关键词
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资金
- NIHR BRC at University College London Hospitals - UK Medical Research Council [MR/P014712/1, MR/V033077/1]
- Rosetrees Trust and Cotswold Trust [A2437]
- Cancer Research UK [C11496/A17786]
- Francis Crick Institute
- UK Medical Research Council [FC001169]
- Wellcome Trust
- Marie Curie ITN Project PLOIDYNET [607722]
- Breast Cancer Research Foundation (BCRF)
- Royal Society Research Professorships Enhancement Award [RP/EA/180007]
- Foulkes Foundation
- NovoNordisk Foundation [ID16584]
- Rosetrees
- NIHR BRC at University College London Hospitals
- National Institute for Health Research
- Rosetrees Trust
- NIHR University College London Hospitals Biomedical Research Centre - Wellcome Trust
- Royal Society [211179/Z/18/Z]
- CRUK University College London Experimental Cancer Medicine Centre
- Royal Society Napier Research Professor
- Wellcome Trust - Cancer Research UK
- (CRUK Cancer Immunotherapy Catalyst Network)
- Cancer Research UK Lung Cancer Centre of Excellence
- Stoneygate Trusts
- CRUK-UCL Centre, Experimental Cancer Medicine Centre
- Stand Up To Cancer-LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant [SU2C-AACR-DT23-17]
- Stand Up To Cancer is a program of the Entertainment Industry Foundation
- Scientific Partner of SU2C
- European Research Council (ERC) under the European Union [FP7-THESEUS-617844]
- European Commission ITN [607722]
- ERC Advanced Grant (PROTEUS) from the European Research Council under the European Union [835297]
- European Union [665233, NCT01888601]
- University College London [UCL/12/0279, 13/LO/1546]
- UCL Cancer Trials Centre
- National Human Genome Research Institute
- Medical Research Council [MR/L016311/1]
- High-Performance Computing at the Francis Crick Institute
- UCL Department of Computer Science Cluster
- CRUK City of London Centre Award [C7893/A26233]
- Bristol-Myers Squibb - Merck and Co.
- Medical Research Council [MR/L016311/1] Funding Source: researchfish
The immune microenvironment plays a crucial role in tumor evolution. The T cell exome TREC tool accurately estimates T cell fraction and shows prognostic value in lung adenocarcinoma. Additionally, tumor TCRA T cell fraction is predictive of response to immunotherapy.
The immune microenvironment influences tumour evolution and can be both prognostic and predict response to immunotherapy(1,2). However, measurements of tumour infiltrating lymphocytes (TI Ls) 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 ofT 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 agnosticto 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 tumour streated 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.
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