Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing
Abstract
Cancer immunotherapies have shown sustained clinical responses in treating non-small-cell lung cancer 1-3, but efficacy varies and depends in part on the amount and properties of tumor infiltrating lymphocytes 4-6. To depict the baseline landscape of the composition, lineage and functional states of tumor infiltrating lymphocytes, here we performed deep single-cell RNA sequencing for 12,346 T cells from 14 treatment-naïve non-small-cell lung cancer patients. Combined expression and T cell antigen receptor based lineage tracking revealed a significant proportion of inter-tissue effector T cells with a highly migratory nature. As well as tumor-infiltrating CD8+ T cells undergoing exhaustion, we observed two clusters of cells exhibiting states preceding exhaustion, and a high ratio of "pre-exhausted" to exhausted T cells was associated with better prognosis of lung adenocarcinoma. Additionally, we observed further heterogeneity within the tumor regulatory T cells (Tregs), characterized by the bimodal distribution of TNFRSF9, an activation marker for antigen-specific Tregs. The gene signature of those activated tumor Tregs, which included IL1R2, correlated with poor prognosis in lung adenocarcinoma. Our study provides a new approach for patient stratification and will help further understand the functional states and dynamics of T cells in lung cancer.
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The aTregs subset overexpressed Foxp3, Cd81, Cd74, and Cst7, together with aTregs-associated genes Tnfrsf4, Tnfrsf9, Tnfrsf18, and Ikzf2.
“activated regulatory T cells (aTregs) overexpressing Foxp3, Cd81, Cd74, and Cst7 genes, together with aTregs-associated genes such as Tnfrsf4, Tnfrsf9, Tnfrsf18, and Ikzf2 (21, 29, 30)”
From Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes (2019) · cites this paper as [30]
rTregs subset expressed higher levels of quiescence genes Ms4a4b and Sell, whereas aTregs subset expressed higher levels of coinhibitory Pdcd1 and Lag3, costimulatory Tnfrsf9 and Tnfrsf4, activation genes S100a11 and Il1r2, and TF Ikzf2.
“whereas the rTregs subset expressed higher levels of quiescence genes (e.g., Ms4a4b and Sell), aTregs subset expressed higher levels of coinhibitory (e.g., Pdcd1 and Lag3) and costimulatory genes [e.g., Tnfrsf9 and Tnfrsf4; (38)], activation genes [S100a11 and Il1r2 (IL1 decoy receptor); (39)], and the transcription factor (TF) Ikzf2 (30).”
From Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes (2019) · cites this paper as [30]
Both aTregs and exhausted cells have been directly implicated in the tumor microenvironment as cells that can suppress tumor immunity, and thus a decline in T cell effector functions along with chronic inflammation and increased frequencies of RECs may play a key role in age-related onset of cancer.
“For example, both aTregs and exhausted cells have been directly implicated in the tumor microenvironment as cells that can suppress tumor immunity (29, 30), and thus a decline in T cell effector functions along with chronic inflammation and increased frequencies of RECs may play a key role in age-related onset of cancer.”
From Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes (2019) · cites this paper as [30]
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Self-citation
- Authors
- Guo, X., Zhang, Y., Zheng, L., Zheng, C., Song, J., Zhang, Q., Kang, B., Liu, Z., Jin, L., Xing, R., Gao, R., Zhang, L., Dong, M., Hu, X., Ren, X., Kirchhoff, D., Roider, H. G., Yan, T., & Zhang, Z.
- Affiliations
- Peking University (CN)
- Peking University Third Hospital (CN)
- Peking University Cancer Hospital (CN)
- Bayer (Germany) (DE)
- Corresponding author
- Yan, Tiansheng
- Zhang, Zemin
- ORCID
- Venue
- Nature Medicine
- Published
- 2018-06-25
- Volume
- 24
- Issue
- 7
- Pages
- 978-985
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2808837841
- Cited by
- 1,651
- References
- 14
- Citations by year
- 2026: 124 · 2025: 209 · 2024: 249 · 2023: 296 · 2022: 283 · 2021: 246 · 2020: 159 · 2019: 67 · 2018: 14
- FWCI
- 46.22
- Type
- journal article
- Language
- en
- Update notices
- correction (2018-08-09)
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- non-small cell lung cancer, tumor-infiltrating lymphocytes, T cell exhaustion, regulatory T cells, 4-1BB, IL1R2, patient stratification, T cell heterogeneity
- MeSH terms
- Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Lymphocyte Activation, Receptors, Antigen, T-Cell, T-Lymphocytes, Sequence Analysis, RNA, CD8-Positive T-Lymphocytes, Cell Proliferation, T-Lymphocytes, Regulatory, Single-Cell Analysis
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