The T cell differentiation landscape is shaped by tumour mutations in lung cancer

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 Galvez-Cancino; Pablo D Becker; Imran Uddin; Mazlina Ismail; Tahel Ronel; Annemarie Woolston; Mariam Jamal-Hanjani; Selvaraju Veeriah; Nicolai J. Birkbak; Gareth A Wilson; Kevin Litchfield; Lucia 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 R. Hadrup; Allan Hackshaw; Karl S Peggs; Nicholas McGranahan; Benny Chain; Charles Swanton; Sergio A Quezada

doi:10.1038/s43018-020-0066-y

The T cell differentiation landscape is shaped by tumour mutations in lung cancer

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 Galvez-Cancino, Pablo D Becker, Imran Uddin, Mazlina IsmailTahel Ronel, Annemarie Woolston, Mariam Jamal-Hanjani, Selvaraju Veeriah, Nicolai J. Birkbak, Gareth A Wilson, Kevin Litchfield, Lucia 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 R. Hadrup, Allan Hackshaw, Karl S Peggs, Nicholas McGranahan, Benny Chain, Charles Swanton, Sergio A Quezada

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Abstract

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.

Original language	English
Journal	Nature Cancer
Volume	1
Issue number	5
Pages (from-to)	546-561
ISSN	2662-1347
DOIs	https://doi.org/10.1038/s43018-020-0066-y
Publication status	Published - 2020

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Ghorani, E., Reading, J. L., Henry, J. Y., de Massy, M. R., Rosenthal, R., Turati, V., Joshi, K., Furness, A. J. S., Aissa, A. B., Saini, S. K., Ramskov, S., Georgiou, A., Sunderland, M. W., Wong, Y. N. S., De Mucha, M. V., Day, W., Galvez-Cancino, F., Becker, P. D., Uddin, I., ... Quezada, S. A. (2020). The T cell differentiation landscape is shaped by tumour mutations in lung cancer. Nature Cancer, 1(5), 546-561. https://doi.org/10.1038/s43018-020-0066-y

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title = "The T cell differentiation landscape is shaped by tumour mutations in lung cancer",

abstract = "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.",

author = "Ehsan Ghorani and Reading, {James L} and Henry, {Jake Y} and {de Massy}, {Marc Robert} and Rachel Rosenthal and Virginia Turati and Kroopa Joshi and Furness, {Andrew J S} and Aissa, {Assma Ben} and Saini, {Sunil Kumar} and Sofie Ramskov and Andrew Georgiou and Sunderland, {Mariana Werner} and Wong, {Yien Ning Sophia} and {De Mucha}, {Maria Vila} and William Day and Felipe Galvez-Cancino and Becker, {Pablo D} and Imran Uddin and Mazlina Ismail and Tahel Ronel and Annemarie Woolston and Mariam Jamal-Hanjani and Selvaraju Veeriah and Birkbak, {Nicolai J.} and Wilson, {Gareth A} and Kevin Litchfield and Lucia Conde and Guerra-Assun{\c c}{\~a}o, {Jos{\'e} Afonso} and Kevin Blighe and Dhruva Biswas and Roberto Salgado and Tom Lund and {Al Bakir}, Maise and Moore, {David A} and Hiley, {Crispin T} and Sherene Loi and Yuxin Sun and Yinyin Yuan and Khalid AbdulJabbar and Samra Turajilic and Javier Herrero and Tariq Enver and Hadrup, {Sine R.} and Allan Hackshaw and Peggs, {Karl S} and Nicholas McGranahan and Benny Chain and Charles Swanton and Quezada, {Sergio A}",

year = "2020",

doi = "10.1038/s43018-020-0066-y",

language = "English",

volume = "1",

pages = "546--561",

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Ghorani, E, Reading, JL, Henry, JY, de Massy, MR, Rosenthal, R, Turati, V, Joshi, K, Furness, AJS, Aissa, AB, Saini, SK, Ramskov, S, Georgiou, A, Sunderland, MW, Wong, YNS, De Mucha, MV, Day, W, Galvez-Cancino, F, Becker, PD, Uddin, I, Ismail, M, Ronel, T, Woolston, A, Jamal-Hanjani, M, Veeriah, S, Birkbak, NJ, Wilson, GA, Litchfield, K, Conde, L, Guerra-Assunção, JA, Blighe, K, Biswas, D, Salgado, R, Lund, T, Al Bakir, M, Moore, DA, Hiley, CT, Loi, S, Sun, Y, Yuan, Y, AbdulJabbar, K, Turajilic, S, Herrero, J, Enver, T, Hadrup, SR, Hackshaw, A, Peggs, KS, McGranahan, N, Chain, B, Swanton, C & Quezada, SA 2020, 'The T cell differentiation landscape is shaped by tumour mutations in lung cancer', Nature Cancer, vol. 1, no. 5, pp. 546-561. https://doi.org/10.1038/s43018-020-0066-y

TY - JOUR

T1 - The T cell differentiation landscape is shaped by tumour mutations in lung cancer

AU - Ghorani, Ehsan

AU - Reading, James L

AU - Henry, Jake Y

AU - de Massy, Marc Robert

AU - Rosenthal, Rachel

AU - Turati, Virginia

AU - Joshi, Kroopa

AU - Furness, Andrew J S

AU - Aissa, Assma Ben

AU - Saini, Sunil Kumar

AU - Ramskov, Sofie

AU - Georgiou, Andrew

AU - Sunderland, Mariana Werner

AU - Wong, Yien Ning Sophia

AU - De Mucha, Maria Vila

AU - Day, William

AU - Galvez-Cancino, Felipe

AU - Becker, Pablo D

AU - Uddin, Imran

AU - Ismail, Mazlina

AU - Ronel, Tahel

AU - Woolston, Annemarie

AU - Jamal-Hanjani, Mariam

AU - Veeriah, Selvaraju

AU - Birkbak, Nicolai J.

AU - Wilson, Gareth A

AU - Litchfield, Kevin

AU - Conde, Lucia

AU - Guerra-Assunção, José Afonso

AU - Blighe, Kevin

AU - Biswas, Dhruva

AU - Salgado, Roberto

AU - Lund, Tom

AU - Al Bakir, Maise

AU - Moore, David A

AU - Hiley, Crispin T

AU - Loi, Sherene

AU - Sun, Yuxin

AU - Yuan, Yinyin

AU - AbdulJabbar, Khalid

AU - Turajilic, Samra

AU - Herrero, Javier

AU - Enver, Tariq

AU - Hadrup, Sine R.

AU - Hackshaw, Allan

AU - Peggs, Karl S

AU - McGranahan, Nicholas

AU - Chain, Benny

AU - Swanton, Charles

AU - Quezada, Sergio A

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

U2 - 10.1038/s43018-020-0066-y

DO - 10.1038/s43018-020-0066-y

M3 - Journal article

C2 - 32803172

VL - 1

SP - 546

EP - 561

JO - Nature Cancer

JF - Nature Cancer

SN - 2662-1347

IS - 5

ER -

The T cell differentiation landscape is shaped by tumour mutations in lung cancer

Abstract

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