Open AccessThe T cell differentiation landscape is shaped by tumour mutations in lung cancer
Author(s) -
Ehsan Ghorani,
James L. Reading,
Jake Y. Henry,
Marc Robert de Massy,
Rachel Rosenthal,
Virginia Turati,
Kroopa Joshi,
Andrew J.S. Furness,
Assma Ben Aissa,
Sunil Kumar Saini,
Sofie Ramskov,
Andrew Georgiou,
Mariana Werner Sunderland,
Yien Ning Sophia Wong,
Maria Vila de Mucha,
William Day,
Felipe Gálvez-Cancino,
Pablo D. Becker,
Imran Uddin,
Theres Oakes,
Maznah Ismail,
Tahel Ronel,
Anne-Marie Woolston,
Mariam JamalHanjani,
Selvaraju Veeriah,
Nicolai J. Birkbak,
Gareth A. Wilson,
Kevin Litchfield,
Lucía Conde,
José Afonso Guerra-Assunção,
Kevin Blighe,
Dhruva Biswas,
Roberto Salgado,
Tom Lund,
Maise Al Bakir,
David A. Moore,
Crispin T. Hiley,
Sherene Loi,
Yuxin Sun,
Yinyin Yuan,
Khalid AbdulJabbar,
Samra Turajilic,
Javier Herrero,
Tariq Enver,
Sine Reker Hadrup,
Allan Hackshaw,
Karl S. Peggs,
Nicholas McGranahan,
Benjamin M. Chain,
Charles Swanton,
Mariam JamalHanjani,
Karl S. Peggs,
Andrew Georgiou,
Mariana Werner Sunderland,
James L. Reading,
Sergio A. Quezada,
Ehsan Ghorani,
Marc Robert de Massy,
David A. Moore,
Allan Hackshaw,
Nicholas McGranahan,
Rachel Rosenthal,
Selvaraju Veeriah,
Dhruva Biswas,
Crispin T. Hiley,
Benjamin M. Chain,
Gareth A. Wilson,
Nicolai J. Birkbak,
Maise Al Bakir,
Kevin Litchfield,
Javier Herrero,
Roberto Salgado,
Yenting Ngai,
Abigail Sharp,
Cristina Rodrigues,
Oliver Pressey,
Sean Smith,
Nicole Gower,
Harjot Kaur Dhanda,
David Lawrence,
Martin Hayward,
Νικόλαος Παναγιωτόπουλος,
Robert George,
Davide Patrini,
Mary Falzon,
Elaine Borg,
Reena Khiroya,
Asia Ahmed,
Magali Taylor,
Junaid Choudhary,
Penny Shaw,
Sam M. Janes,
Martin Förster,
Tanya Ahmad,
Siow Ming Lee,
Dawn Carnell,
R. Mendes,
Jeremy George,
Neal Navani,
Marco Scarci,
Elisa Bertoja,
Robert Stephens,
Emilie Martii Hoogenboom,
James W. Holding,
Steve Bandula,
Thomas B.K. Watkins,
Mickael Escudero,
Aengus Stewart,
Andrew Rowan,
Jacki Goldman,
Peter Van Loo,
Richard Stone,
Tamara Denner,
Emma Nye,
Sophia Ward,
Emilia L. Lim,
Stefan Boeing,
Maria Greco,
Jérôme Nicod,
Clare Puttick,
Katey S.S. Enfield,
Emma Colliver,
Brittany Campbell,
Chris Abbosh,
Yin Wu,
Marcin Skrzypski,
Robert E. Hynds,
Teresa Marafioti,
John A. Hartley,
Pat Gorman,
Helen Lowe,
Leah Ensell,
Victoria J. Spanswick,
Angeliki Karamani,
Maryam Razaq,
Stephan Beck,
Ariana Huebner,
Michelle Dietzen,
CristiceurLombardelli,
Mita Afroza Akther,
HaoRan Zhai,
Nnennaya Kannu,
Elizabeth Manzano,
Supreet Kaur Bola,
Elena Hoxha,
Emine Hatipoglu,
Stephanie Ogwuru,
Gillian Price,
Sylvie Dubois-Marshall,
Keith M. Kerr,
Shirley Palmer,
Heather Cheyne,
J. Richard Miller,
Keith Buchan,
Mahendran Chetty,
Mohammed Khalil,
Veni Ezhil,
Vineet Prakash,
Girija Anand,
Sajid Khan,
Kelvin Lau,
Michael Sheaff,
Peter Schmid,
Louise Lim,
John Conibear,
Roland F. Schwarz,
Jonathan Tugwood,
Jackie Pierce,
Caroline Dive,
Ged Brady,
Dominic G. Rothwell,
Francesca Chemi,
Elaine Kilgour,
Fiona Blackhall,
Lynsey Priest,
Matthew Krebs,
Philip Crosbie,
John Le Quesne,
Joan Riley,
Lindsay Primrose,
Luke Martinson,
Nicolas Carey,
Jacqui A. Shaw,
Dean A. Fennell,
Apostolos Nakas,
Sridhar Rathinam,
Louise Nelson,
Kim Ryanna,
Mohamad Tuffail,
Amrita Bajaj,
Fiona J. E. Morgan,
Malgorzata Kornaszewska,
Richard Attanoos,
Haydn Adams,
Helen Davies,
Mathew Carter,
Colin R. Lindsay,
Fábio Gomes,
Zoltán Szállási,
István Csabai,
Miklós Dióssy,
Hugo J.W.L. Aerts,
Alan Kirk,
Mo Asif,
J. A. V. Butler,
Rocco Bilanca,
Nikos Kostoulas,
Mairead MacKenzie,
Maggie Wilcox,
Sara Busacca,
Alan G. Dawson,
Mark R. Lovett,
Michael Shackcloth,
Sarah Feeney,
Julius Asante-Siaw,
John R. Gosney,
Angela Leek,
Nicola Totten,
Jack Davies Hodgkinson,
Rachael Waddington,
Jane Rogan,
Katrina Moore,
William Monteiro,
Hilary Marshall,
Kevin G. Blyth,
Craig Dick,
Andrew Kidd,
Eric Lim,
Paulo De Sousa,
Simon Jordan,
Alexandra Rice,
Hilgardt Raubenheimer,
Harshil Bhayani,
Morag Hamilton,
Lyn Ambrose,
Anand Devaraj,
Hema Chavan,
Sofina Begum,
Aleksander Mani,
Daniel Kaniu,
Mpho Malima,
Sarah Booth,
Andrew G. Nicholson,
Nadia Fernandes,
Jessica E. Wallen,
Pratibha Shah,
Sarah Danson,
Jonathan Bury,
John F. 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,
Teresa Light,
Tracey Horey,
Dionysis Papadatos-Pastos,
Peter Russell,
S. Löck,
Kayleigh Gilbert,
Babu Naidu,
Gerald Langman,
Andrew Robinson,
Hollie Bancroft,
Amy Kerr,
Salma Kadiri,
Charlotte Ferris,
Gary Middleton,
Madava Djearaman,
Akshay J. Patel,
Christian H. Ottensmeier,
Serena Chee,
Benjamin Johnson,
Aiman Alzetani,
Emily Shaw,
J.F. Lester,
Yvonne Summers,
Raffaele Califano,
Paul Taylor,
Rajesh Shah,
Piotr Krysiak,
Kendadai Rammohan,
Eustace Fontaine,
Richard Booton,
Matthew Evison,
Stuart B. Moss,
Juliette Novasio,
Leena Dennis Joseph,
Paul Bishop,
Anshuman Chaturvedi,
Helen Doran,
Felice Granato,
Vijay Joshi,
Elaine Smith,
Ángeles Montero,
Charles Swanton,
Sergio A. Quezada
Publication year - 2020
Publication title -
nature cancer
Language(s) - English
Resource type - Journals
ISSN - 2662-1347
DOI - 10.1038/s43018-020-0066-y
Subject(s) - cd8 , biology , progenitor cell , cancer research , cytotoxic t cell , lung cancer , immunotherapy , t cell , cell , flow cytometry , phenotype , exome sequencing , antigen , immunology , immune system , gene , stem cell , genetics , medicine , oncology , in vitro
Tumour mutational burden (TMB) predicts immunotherapy outcome in non-small cell lung cancer (NSCLC), consistent with immune recognition of tumour neoantigens. However, persistent antigen exposure is detrimental for T cell function. How TMB affects CD4 and CD8 T cell differentiation in untreated tumours, and whether this affects patient outcomes is unknown. Here we paired high-dimensional flow cytometry, exome, single-cell and bulk RNA sequencing from patients with resected, untreated NSCLC to examine these relationships. TMB was associated with compartment-wide T cell differentiation skewing, characterized by loss of TCF7-expressing progenitor-like CD4 T cells, and an increased abundance of dysfunctional CD8 and CD4 T cell subsets, with significant phenotypic and transcriptional similarity to neoantigen-reactive CD8 T cells. A gene signature of redistribution from progenitor-like to dysfunctional states associated with poor survival in lung and other cancer cohorts. Single-cell characterization of these populations informs potential strategies for therapeutic manipulation in NSCLC.