Temporal single-cell tracing reveals clonal revival and expansion of precursor exhausted T cells during anti-PD-1 therapy in lung cancer
Open accessAbstract
Anti-PD-1 treatment has shown unprecedented clinical success in the treatment of non-small-cell lung cancer (NSCLC), but the underlying mechanisms remain incompletely understood. Here, we performed temporal single-cell RNA and paired T-cell receptor sequencing on 47 tumor biopsies from 36 patients with NSCLC following PD-1-based therapies. We observed increased levels of precursor exhausted T (Texp) cells in responsive tumors after treatment, characterized by low expression of coinhibitory molecules and high expression of GZMK . By contrast, nonresponsive tumors failed to accumulate Texp cells. Our data suggested that Texp cells were unlikely to be derived from the reinvigoration of terminally exhausted cells; instead, they were accumulated by (1) local expansion and (2) replenishment by peripheral T cells with both new and pre-existing clonotypes, a phenomenon we named clonal revival. Our study provides insights into mechanisms underlying PD-1-based therapies, implicating clonal revival and expansion of Texp cells as steps to improve NSCLC treatment.
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Applying ICB and combination therapies as neoadjuvant treatments provides an opportunity to observe immune cell dynamics in the tumor microenvironment with temporal samples.
“Applying ICB and combination therapies as neoadjuvant treatments provides an opportunity to observe immune cell dynamics in tumor microenvironment (TME) with temporal samples.”
From Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer (2025) · cites this paper as [18]
The introduction (p. 1) says the authors used tumor biopsies collected at multiple treatment time points to study T-cell dynamics during anti-PD-1 plus chemotherapy. The Methods (p. 11) describe that combination treatment, but our copy does not identify it as neoadjuvant treatment. Thus the temporal-sampling point is supported, while the neoadjuvant qualifier is not. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCD8+ T cells, primary targets for PD-1 blockade, show favorable responses across cancer types, including local clonal expansion and recruitment of circulating T cells.
“CD8+ T cells, primary targets for PD-1 blockade, show favorable responses across cancer types, including local clonal expansion and recruitment of circulating T cells.”
From Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer (2025) · cites this paper as [18]
The paper’s summary (p. 1) and Fig. 7 description (p. 10) link response to anti-PD-1 therapy in non-small-cell lung cancer with local expansion of precursor exhausted CD8+ T cells and replenishment by peripheral T cells. The claim extends this finding across cancer types, which the study does not establish; the discussion on p. 10 also says the direction of T-cell migration needs more direct confirmation. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThese CD8+ T cell subsets show different responses to anti-PD(L)-1 therapies, with TCF7+ Tpex cells demonstrated critical for ICB response in mouse tumor models and cancers.
“These cell subsets show different responses to anti-PD(L)-1 therapies,”
From Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer (2025) · cites this paper as [18]
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- Authors
- Liu, B., Hu, X., Feng, K., Gao, R., Xue, Z., Zhang, S., Zhang, Y., Corse, E., Hu, Y., Han, W., & Zhang, Z.
- Affiliations
- Peking University (CN)
- Chinese PLA General Hospital (CN)
- Boehringer Ingelheim (United States) (US)
- Corresponding author
- Han, Weidong
- Zhang, Zemin
- ORCID
- Venue
- Nature Cancer
- Published
- 2021-12-23
- Volume
- 3
- Issue
- 1
- Pages
- 108-121
- ISSN
- 2662-1347 (ISSN-L)
- OpenAlex
- W4200168331
- Cited by
- 473
- References
- 20
- Citations by year
- 2026: 91 · 2025: 119 · 2024: 123 · 2023: 117 · 2022: 23
- FWCI
- 24.30
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Cancer (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Greater South Information System
- Funders
- National Natural Science Foundation of China (91942307, 31991171, 81988101, 91742203)
- Beijing advanced Innovation Center for Genomics
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- anti-PD-1 therapy, non-small cell lung cancer, T cell exhaustion, T cell clonal expansion, tumor immune microenvironment, granzyme K, co-inhibitory molecules, T cell clonotypes, immune checkpoint inhibitors, treatment response mechanisms
- MeSH terms
- Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Receptors, Antigen, T-Cell, T-Lymphocytes, Programmed Cell Death 1 Receptor
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