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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-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.

Titel:	Using DNA sequencing data to quantify T cell fraction and therapy response.
Autor/in / Beteiligte Person:	Bentham, R ; Litchfield, K ; Watkins, TBK ; Lim, EL ; Rosenthal, R ; Martínez-Ruiz, C ; Hiley, CT ; Bakir, MA ; Salgado, R ; Moore, DA ; Jamal-Hanjani, M ; Swanton, C ; McGranahan, N
Link:	Zum Volltext
Zeitschrift:	Nature, Jg. 597 (2021-09-01), Heft 7877, S. 555-560
Veröffentlichung:	Basingstoke : Nature Publishing Group ; <i>Original Publication</i>: London, Macmillan Journals ltd., 2021
Medientyp:	academicJournal
ISSN:	1476-4687 (electronic)
DOI:	10.1038/s41586-021-03894-5
Schlagwort:	Adenocarcinoma of Lung diagnosis Adenocarcinoma of Lung genetics Adenocarcinoma of Lung immunology Adenocarcinoma of Lung therapy Aspartic Acid Endopeptidases genetics Cohort Studies Exome genetics Female Humans Lymphocytes, Tumor-Infiltrating immunology Male Mutation Neoplasms diagnosis Neoplasms genetics Prognosis Receptors, Antigen, T-Cell, alpha-beta genetics Exome Sequencing economics Immunotherapy Neoplasms immunology Neoplasms therapy T-Lymphocytes cytology T-Lymphocytes metabolism
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Corporate Authors: TRACERx Consortium Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Nature] 2021 Sep; Vol. 597 (7877), pp. 555-560. <i>Date of Electronic Publication: </i>2021 Sep 08. MeSH Terms: Immunotherapy* ; Neoplasms / immunology ; Neoplasms / therapy ; T-Lymphocytes / cytology ; T-Lymphocytes / metabolism ; Adenocarcinoma of Lung / diagnosis ; Adenocarcinoma of Lung / genetics ; Adenocarcinoma of Lung / immunology ; Adenocarcinoma of Lung / therapy ; Aspartic Acid Endopeptidases / genetics ; Cohort Studies ; Exome / genetics ; Female ; Humans ; Lymphocytes, Tumor-Infiltrating / immunology ; Male ; Mutation ; Neoplasms / diagnosis ; Neoplasms / genetics ; Prognosis ; Receptors, Antigen, T-Cell, alpha-beta / genetics ; Exome Sequencing / economics References: Rosenthal, R. et al. Neoantigen-directed immune escape in lung cancer evolution. Nature 567, 479–485 (2019). 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(PMID: 2736349110.1038/modpathol.2016.109) Grant Information: 19278 United Kingdom CRUK_ Cancer Research UK; MR/L016311/1 United Kingdom MRC_ Medical Research Council; MR/P014712/1 United Kingdom MRC_ Medical Research Council; 25223 United Kingdom CRUK_ Cancer Research UK; 25253 United Kingdom CRUK_ Cancer Research UK; 20466 United Kingdom CRUK_ Cancer Research UK; 17786 United Kingdom CRUK_ Cancer Research UK; 30025 United Kingdom CRUK_ Cancer Research UK; 30194 United Kingdom CRUK_ Cancer Research UK; MR/V033077/1 United Kingdom MRC_ Medical Research Council; 24956 United Kingdom CRUK_ Cancer Research UK; 211179/Z/18/Z United Kingdom WT_ Wellcome Trust Contributed Indexing: Investigator: NJ Birkbak; M Escudero; A Stewart; A Rowan; J Goldman; P Van Loo; RK Stone; T Denner; E Nye; S Ward; S Boeing; M Greco; J Nicod; C Puttick; K Enfield; E Colliver; B Campbell; AM Frankell; D Cook; M Angelova; A Magness; C Bailey; A Toncheva; K Dijkstra; J Kisistok; M Sokac; O Pich; J Demeulemeester; EL Cadieux; C Castignani; K Thakkar; H Fu; T Karasaki; O Al-Sawaf; MS Hill; C Abbosh; Y Wu; S Veeriah; RE Hynds; A Georgiou; M Werner Sunderland; JL Reading; SA Quezada; KS Peggs; T Marafioti; JA Hartley; HL Lowe; L Ensell; V Spanswick; A Karamani; D Biswas; S Beck; O Chervova; M Tanic; A Huebner; M Dietzen; JRM Black; C Naceur-Lombardelli; MA Akther; H Zhai; N Kanu; S Summan; F Gimeno-Valiente; K Chen; E Manzano; S Kaur Bola; E Ghorani; MR de Massy; E Hoxha; E Hatipoglu; B Chain; DR Pearce; J Herrero; S Zaccaria; J Lester; F Morgan; M Kornaszewska; R Attanoos; H Adams; H Davies; JA Shaw; J Riley; L Primrose; D Fennell; A Nakas; S Rathinam; R Plummer; R Boyles; M Tufail; A Bajaj; J Brozik; K Ang; MF Chowdhry; W Monteiro; H Marshall; A Dawson; S Busacca; D Marrone; C Smith; G Anand; S Khan; G Price; M Khalil; K Kerr; S Richardson; H Cheyne; J Miller; K Buchan; M Chetty; S Dubois-Marshall; S Lock; K Gilbert; B Naidu; G Langman; H Bancroft; S Kadiri; G Middleton; M Djearaman; A Osman; H Shackleford; A Patel; A Leek; N Totten; JD Hodgkinson; J Rogan; K Moore; R Waddington; R Califano; R Shah; P Krysiak; K Rammohan; E Fontaine; R Booton; M Evison; S Moss; J Novasio; L Joseph; P Bishop; A Chaturvedi; H Doran; F Granato; V Joshi; E Smith; A Montero; P Crosbie; F Blackhall; L Priest; MG Krebs; C Dive; DG Rothwell; A Kerr; E Kilgour; K Baker; M Carter; CR Lindsay; F Gomes; J Tugwood; J Pierce; A Clipson; R Schwarz; TL Kaufmann; M Huska; Z Szallasi; I Csabai; M Diossy; H Aerts; C Fekete; G Royle; C Veiga; M Skrzypski; D Lawrence; M Hayward; N Panagiotopoulos; R George; D Patrini; M Falzon; E Borg; R Khiroya; A Ahmed; M Taylor; J Choudhary; SM Janes; M Forster; T Ahmad; SM Lee; N Navani; D Papadatos-Pastos; M Scarci; P Gorman; E Bertoja; RCM Stephens; EM Hoogenboom; JW Holding; S Bandula; R Thakrar; R Anand; K Selvaraju; J Wilson; S Hessey; P Ashford; M Shah; MV Duran; M MacKenzie; M Wilcox; A Hackshaw; Y Ngai; A Sharp; C Rodrigues; O Pressey; S Smith; N Gower; HK Dhanda; K Chan; S Chakraborty; C Ottensmeier; S Chee; B Johnson; A Alzetani; J Cave; L Scarlett; E Shaw; E Lim; P De Sousa; S Jordan; A Rice; H Raubenheimer; H Bhayani; M Hamilton; L Ambrose; A Devaraj; H Chavan; S Begum; SI Buderi; D Kaniu; M Malima; S Booth; AG Nicholson; N Fernandes; C Deeley; P Shah; C Proli; K Lau; M Sheaff; P Schmid; L Lim; J Conibear; M Hewish; S Danson; J Bury; J Edwards; J Hill; S Matthews; Y Kitsanta; J Rao; S Tenconi; L Socci; K Suvarna; F Kibutu; P Fisher; R Young; J Barker; F Taylor; K Lloyd; M Shackcloth; J Asante-Siaw; J Gosney; T Light; T Horey; P Russell; D Papadatos-Pastos; KG Blyth; C Dick; A Kidd; A Kirk; M Asif; J Butler; R Bilancia; N Kostoulas; M Thomas; GA Wilson Substance Nomenclature: 0 (Receptors, Antigen, T-Cell, alpha-beta) ; EC 3.4.23.- (Aspartic Acid Endopeptidases) ; EC 3.4.23.- (signal peptide peptidase like 3, human) Entry Date(s): Date Created: 20210909 Date Completed: 20220204 Latest Revision: 20240306 Update Code: 20240306

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