The T cell differentiation landscape is shaped by tumour mutations in lung cancer
Authors listEhsan Ghorani James L Reading Jake Y Henry Marc Robert de Massy Rachel Rosenthal Virginia Turati Kroopa Joshi Andrew JS 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 Theres Oakes Mazlina Ismail Tahel Ronel Annemarie Woolston Mariam Jamal-Hanjani Selvaraju Veeriah Nicolai Birkbak Gareth 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 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.
Journal Nature Cancer
Issue number 5