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Updated: Dec 11, 2025

Multidimensional Coculture System to Model Lung Squamous Carcinoma Progression
Published on: March 17, 2020
The T cell differentiation landscape is shaped by tumour mutations in lung cancer
Ehsan Ghorani1,2, James L Reading3,4, Jake Y Henry1,2
1Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK.
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.
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