학술논문
The T cell differentiation landscape is shaped by tumour mutations in lung cancer
Document Type
Original Paper
Author
Ghorani, Ehsan; Reading, James L.; Henry, Jake Y.; Massy, Marc Robert de; Rosenthal, Rachel; Turati, Virginia; Joshi, Kroopa; Furness, Andrew J. S.; Ben Aissa, Assma; Saini, Sunil Kumar; Ramskov, Sofie; Georgiou, Andrew; Sunderland, Mariana Werner; Wong, Yien Ning Sophia; Mucha, Maria Vila De; Day, William; Galvez-Cancino, Felipe; Becker, Pablo D.; Uddin, Imran; Oakes, Theres; Ismail, Mazlina; Ronel, Tahel; Woolston, Annemarie; Jamal-Hanjani, Mariam; Veeriah, Selvaraju; Birkbak, Nicolai J.; Wilson, Gareth A.; Litchfield, Kevin; Conde, Lucia; Guerra-Assunção, José Afonso; Blighe, Kevin; Biswas, Dhruva; Salgado, Roberto; Lund, Tom; Bakir, Maise Al; Moore, David A.; Hiley, Crispin T.; Loi, Sherene; Sun, Yuxin; Yuan, Yinyin; AbdulJabbar, Khalid; Turajilic, Samra; Herrero, Javier; Enver, Tariq; Hadrup, Sine R.; Hackshaw, Allan; Peggs, Karl S.; McGranahan, Nicholas; Chain, Benny; Swanton, Charles; Quezada, Sergio A.
Source
Nature Cancer. 1(5):546-561
Subject
Language
English
ISSN
2662-1347
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 strong phenotypic and transcriptional similarity to neoantigen-reactive CD8 T cells. A gene signature of redistribution from progenitor-like to dysfunctional states was associated with poor survival in lung and other cancer cohorts. Single-cell characterization of these populations informs potential strategies for therapeutic manipulation in NSCLC.
Ghorani et al. use a multiomics approach to characterize the effect of tumour mutational burden on the differentiation of CD4 and CD8 T cell subpopulations in non-small cell lung cancer.
Ghorani et al. use a multiomics approach to characterize the effect of tumour mutational burden on the differentiation of CD4 and CD8 T cell subpopulations in non-small cell lung cancer.