The T cell differentiation landscape is shaped by tumour mutations in lung cancer.
Ghorani E., Reading JL., Henry JY., Massy MRD., Rosenthal R., Turati V., Joshi K., Furness AJS., Ben Aissa A., Saini SK., Ramskov S., Georgiou A., Sunderland MW., Wong YNS., Mucha MVD., Day W., Galvez-Cancino F., Becker PD., Uddin I., Oakes T., Ismail M., Ronel T., Woolston A., Jamal-Hanjani M., Veeriah S., Birkbak NJ., Wilson GA., Litchfield K., Conde L., Guerra-Assunção JA., Blighe K., Biswas D., Salgado R., Lund T., Bakir MA., Moore DA., Hiley CT., Loi S., Sun Y., Yuan Y., AbdulJabbar K., Turajilic S., Herrero J., Enver T., Hadrup SR., Hackshaw A., Peggs KS., McGranahan N., Chain B., TRACERx Consortium None., Swanton C., Quezada SA.
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.