Abstract
Understanding of the functional states and clonal dynamics of T cells after immune checkpoint blockade (ICB) is valuable for improving these therapeutic strategies. Here we performed Smart-seq2 single-cell RNA sequencing (scRNA-seq) analysis on 3,110 peripheral T cells of non-small cell lung cancer (NSCLC) patients before and after the initiation of programmed cell death protein 1 (PD-1) blockade. We identified individual peripheral T cell clones based on the full-length T cell receptor (TCR) sequences and monitored their dynamics during immunotherapy. We found a higher cytotoxic activity in the tumor-related CD4+ T cell clones than in the CD8+ T cell clones. Based on a large tumor-related CD4+ T cell clone, we observed a dramatically decreased abundance after progression, as well as a reduction in the percentage of PD-1+ T cells. We also detected 25 genes, such as CXCR4, DUSP2 and ZFP36, that were noticeably upregulated or downregulated following progression. In addition, the pseudotime trajectory of CD8+ T cell clones corresponded to the treatment time points, showing a decreased activity in the "cytokine and cytokine receptor interaction" pathway. These analyses provided an insight into the dynamics of peripheral T cell clones during PD-1 blockade in NSCLC.
Keywords:
Cancer immunotherapy; Non-small cell lung cancer; PD-1; Single cell sequencing.
MeSH terms
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Aged
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Antineoplastic Agents, Immunological / pharmacology
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Antineoplastic Agents, Immunological / therapeutic use*
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / drug effects
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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Carcinoma, Non-Small-Cell Lung / blood
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Carcinoma, Non-Small-Cell Lung / diagnosis
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Carcinoma, Non-Small-Cell Lung / drug therapy*
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Carcinoma, Non-Small-Cell Lung / immunology
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Clinical Trials, Phase III as Topic
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Disease Progression
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Lung / diagnostic imaging
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Lung / pathology
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Lung Neoplasms / blood
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Lung Neoplasms / diagnosis
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / immunology
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Male
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Middle Aged
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Multicenter Studies as Topic
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Nivolumab / pharmacology
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Nivolumab / therapeutic use
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Programmed Cell Death 1 Receptor / antagonists & inhibitors*
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Programmed Cell Death 1 Receptor / immunology
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Programmed Cell Death 1 Receptor / metabolism
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RNA-Seq
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Randomized Controlled Trials as Topic
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Receptors, Antigen, T-Cell / genetics
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Receptors, Antigen, T-Cell / metabolism
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Single-Cell Analysis
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T-Lymphocyte Subsets / drug effects*
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
Substances
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Antineoplastic Agents, Immunological
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PDCD1 protein, human
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Programmed Cell Death 1 Receptor
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Receptors, Antigen, T-Cell
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Nivolumab