TY - JOUR
T1 - The T cell differentiation landscape is shaped by tumour mutations in lung cancer
AU - TRACERx Consortium
AU - Ghorani, Ehsan
AU - Reading, James L
AU - Henry, Jake Y
AU - Massy, Marc Robert de
AU - Rosenthal, Rachel
AU - Turati, Virginia
AU - Joshi, Kroopa
AU - Furness, Andrew J S
AU - Ben Aissa, Assma
AU - Saini, Sunil Kumar
AU - Ramskov, Sofie
AU - Georgiou, Andrew
AU - Sunderland, Mariana Werner
AU - Wong, Yien Ning Sophia
AU - Mucha, Maria Vila De
AU - Day, William
AU - Galvez-Cancino, Felipe
AU - Becker, Pablo D
AU - Uddin, Imran
AU - Oakes, Theres
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 - Bakir, Maise Al
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
PY - 2020/5/1
Y1 - 2020/5/1
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.
KW - B7-H1 Antigen/genetics
KW - Biomarkers, Tumor/genetics
KW - Carcinoma, Non-Small-Cell Lung/genetics
KW - Cell Differentiation/genetics
KW - Humans
KW - Lung Neoplasms/genetics
KW - Mutation
UR - http://www.scopus.com/inward/record.url?scp=85090244194&partnerID=8YFLogxK
U2 - 10.1038/s43018-020-0066-y
DO - 10.1038/s43018-020-0066-y
M3 - Article
C2 - 32803172
SN - 2662-1347
VL - 1
SP - 546
EP - 561
JO - Nature Cancer
JF - Nature Cancer
IS - 5
ER -
