The T cell differentiation landscape is shaped by tumour mutations in lung cancer
- 22 May 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Cancer
- Vol. 1 (5), 546-561
- https://doi.org/10.1038/s43018-020-0066-y
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.Keywords
This publication has 87 references indexed in Scilit:
- Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patientsJCI Insight, 2011
- Role of antigen persistence and dose for CD4+T-cell exhaustion and recoveryProceedings of the National Academy of Sciences of the United States of America, 2010
- Bystander killing of cancer requires the cooperation of CD4+ and CD8+ T cells during the effector phaseThe Journal of Experimental Medicine, 2010
- Molecular Signature of CD8+ T Cell Exhaustion during Chronic Viral InfectionImmunity, 2007
- Heterogeneity and Cell-Fate Decisions in Effector and Memory CD8+ T Cell Differentiation during Viral InfectionImmunity, 2007
- Recognition of HIV-1 Peptides by Host CTL Is Related to HIV-1 Similarity to Human ProteinsPLOS ONE, 2007
- Progressive CD4+ central–memory T cell decline results in CD4+ effector–memory insufficiency and overt disease in chronic SIV infectionThe Journal of Experimental Medicine, 2007
- PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progressionNature, 2006
- Cognate CD4+ T cell licensing of dendritic cells in CD8+ T cell immunityNature Immunology, 2004
- Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cellsBlood, 2003