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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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 languageEnglish
JournalNature Cancer
Issue number5
Pages (from-to)546-561
Publication statusPublished - 2020


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