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, Nicolai J. Birkbak, Mickael Escudero, Aengus Stewart, Andrew Rowan, Jacki Goldman, Peter Van Loo, Richard Kevin Stone, Tamara Denner, Emma Nye, Sophia Ward, Stefan Boeing, Maria Greco, Jerome Nicod, Clare Puttick, Katey Enfield, Emma Colliver, Brittany Campbell, Alexander M. Frankell, Daniel Cook, Mihaela Angelova, Alastair Magness, Chris Bailey, Antonia Toncheva, Krijn Dijkstra, Judit Kisistok, Mateo Sokac, Oriol Pich, Jonas Demeulemeester, Elizabeth Larose Cadieux, Carla Castignani, Krupa Thakkar, Hongchang Fu, Takahiro Karasaki, Othman Al-Sawaf, Mark S. Hill, Christopher Abbosh, Yin Wu, Selvaraju Veeriah, Robert E. Hynds, Andrew Georgiou, Mariana Werner Sunderland, James L. Reading, Sergio A. Quezada, Karl S. Peggs, Teresa Marafioti, John A. Hartley, Helen L. Lowe, Leah Ensell, Victoria Spanswick, Angeliki Karamani, Dhruva Biswas, Stephan Beck, Olga Chervova, Miljana Tanic, Ariana Huebner, Michelle Dietzen, James R. M. Black, Cristina Naceur-Lombardelli, Mita Afroza Akther, Haoran Zhai, Nnennaya Kanu, Simranpreet Summan, Francisco Gimeno-Valiente, Kezhong Chen, Elizabeth Manzano, Supreet Kaur Bola, Ehsan Ghorani, Marc Robert de Massy, Elena Hoxha, Emine Hatipoglu, Benny Chain, David R. Pearce, Javier Herrero, Simone Zaccaria, Jason Lester, Fiona Morgan, Malgorzata Kornaszewska, Richard Attanoos, Haydn Adams, Helen Davies, Jacqui A. Shaw, Joan Riley, Lindsay Primrose, Dean Fennell, Apostolos Nakas, Sridhar Rathinam, Rachel Plummer, Rebecca Boyles, Mohamad Tufail, Amrita Bajaj, Jan Brozik, Keng Ang, Mohammed Fiyaz Chowdhry, William Monteiro, Hilary Marshall, Alan Dawson, Sara Busacca, Domenic Marrone, Claire Smith, Girija Anand, Sajid Khan, Gillian Price, Mohammed Khalil, Keith Kerr, Shirley Richardson, Heather Cheyne, Joy Miller, Keith Buchan, Mahendran Chetty, Sylvie Dubois-Marshall, Sara Lock, Kayleigh Gilbert, Babu Naidu, Gerald Langman, Hollie Bancroft, Salma Kadiri, Gary Middleton, Madava Djearaman, Aya Osman, Helen Shackleford, Akshay Patel, Angela Leek, Nicola Totten, Jack Davies Hodgkinson, Jane Rogan, Katrina Moore, Rachael Waddington, Raffaele Califano, Rajesh Shah, Piotr Krysiak, Kendadai Rammohan, Eustace Fontaine, Richard Booton, Matthew Evison, Stuart Moss, Juliette Novasio, Leena Joseph, Paul Bishop, Anshuman Chaturvedi, Helen Doran, Felice Granato, Vijay Joshi, Elaine Smith, Angeles Montero, Philip Crosbie, Fiona Blackhall, Lynsey Priest, Matthew G. Krebs, Caroline Dive, Dominic G. Rothwell, Alastair Kerr, Elaine Kilgour, Katie Baker, Mathew Carter, Colin R. Lindsay, Fabio Gomes, Jonathan Tugwood, Jackie Pierce, Alexandra Clipson, Roland Schwarz, Tom L. Kaufmann, Matthew Huska, Zoltan Szallasi, Istvan Csabai, Miklos Diossy, Hugo Aerts, Charles Fekete, Gary Royle, Catarina Veiga, Marcin Skrzypski, David Lawrence, Martin Hayward, Nikolaos Panagiotopoulos, Robert George, Davide Patrini, Mary Falzon, Elaine Borg, Reena Khiroya, Asia Ahmed, Magali Taylor, Junaid Choudhary, Sam M. Janes, Martin Forster, Tanya Ahmad, Siow Ming Lee, Neal Navani, Dionysis Papadatos-Pastos, Marco Scarci, Pat Gorman, Elisa Bertoja, Robert C. M. Stephens, Emilie Martinoni Hoogenboom, James W. Holding, Steve Bandula, Ricky Thakrar, Radhi Anand, Kayalvizhi Selvaraju, James Wilson, Sonya Hessey, Paul Ashford, Mansi Shah, Marcos Vasquez Duran, Mairead MacKenzie, Maggie Wilcox, Allan Hackshaw, Yenting Ngai, Abigail Sharp, Cristina Rodrigues, Oliver Pressey, Sean Smith, Nicole Gower, Harjot Kaur Dhanda, Kitty Chan, Sonal Chakraborty, Christian Ottensmeier, Serena Chee, Benjamin Johnson, Aiman Alzetani, Judith Cave, Lydia Scarlett, Emily Shaw, Eric Lim, Paulo De Sousa, Simon Jordan, Alexandra Rice, Hilgardt Raubenheimer, Harshil Bhayani, Morag Hamilton, Lyn Ambrose, Anand Devaraj, Hema Chavan, Sofina Begum, Silviu I. Buderi, Daniel Kaniu, Mpho Malima, Sarah Booth, Andrew G. Nicholson, Nadia Fernandes, Christopher Deeley, Pratibha Shah, Chiara Proli, Kelvin Lau, Michael Sheaff, Peter Schmid, Louise Lim, John Conibear, Madeleine Hewish, Sarah Danson, Jonathan Bury, John Edwards, Jennifer Hill, Sue Matthews, Yota Kitsanta, Jagan Rao, Sara Tenconi, Laura Socci, Kim Suvarna, Faith Kibutu, Patricia Fisher, Robin Young, Joann Barker, Fiona Taylor, Kirsty Lloyd, Michael Shackcloth, Julius Asante-Siaw, John Gosney, Teresa Light, Tracey Horey, Peter Russell, Dionysis Papadatos-Pastos, Kevin G. Blyth, Craig Dick, Andrew Kidd, Alan Kirk, Mo Asif, John Butler, Rocco Bilancia, Nikos Kostoulas, Mathew Thomas, Gareth A. Wilson, Charles Swanton, Nicholas McGranahan

16
Sep 8, 2021
Nature
DOI :
10.1038/s41586-021-03894-5
Article show_chart
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.
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