Ghorani, E;
Reading, JL;
Henry, JY;
Massy, MRD;
Rosenthal, R;
Turati, V;
Joshi, K;
... Quezada, SA; + view all
(2020)
The T cell differentiation landscape is shaped by tumour mutations in lung cancer.
Nature Cancer
, 1
(5)
pp. 546-561.
10.1038/s43018-020-0066-y.
Preview |
Text
Reading_The T cell differentiation landscape is shaped by tumour mutations in lung cancer_AAM2.pdf - Accepted Version Download (21MB) | Preview |
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.
Archive Staff Only
 |
View Item |
