Dynamics of peripheral T cell clones during PD-1 blockade in non-small cell lung cancer

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.

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Data availability

Sequencing raw data is available at GSA (Genome Sequence Archive in BIG Data Center, Beijing Institute of Genomics, Chinese Academy of Sciences). The accession number is HRA000104. Gene expression profiling of individual T cell clones at different time points can be explored on https://118.190.148.166:3838/lcpd.

Abbreviations

DEG:

Differentially expressed gene

ICB:

Immune checkpoint blockade

NSCLC:

Non-small cell lung cancer

PD-1:

Programmed cell death protein 1

PD-L1:

Programmed death-ligand 1

scRNA-seq:

Single-cell RNA sequencing

TCR:

T cell receptor

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Acknowledgements

We thank Xuefang Zhang and Fei Wang for assistance with flow cytometry. We thank the Computing Platform of the CLS (Peking University).

Funding

This project was supported by Beijing Advanced Innovation Center for Genomics at Peking University, National Natural Science Foundation of China (31530036, 91742203, 91942307, 81988101, 81630071), National Key Research and Development Project (2019YFC1315700) and CAMS Innovation Fund for Medical Sciences (CIFMS 2016-I2M-3-008).

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Contributions

XH and JW designed experiments. RG and XH performed the experiments. FZ analyzed sequencing data. HB, KF and JD collected clinical samples. FZ and XH wrote the initial draft of the manuscript. HB, KF, ZZ and JW contributed to analysis and interpretation of data, and critically reviewed the manuscript. All authors approved the final version of the manuscript.

Corresponding authors

Correspondence to Jie Wang or Xueda Hu.

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The authors report no financial interests or potential conflicts of interests.

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This study was approved by the Research and Ethical Committee of Cancer Hospital, Chinese Academy of Medical Sciences, China and complied with relevant ethical regulations.

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Written informed consents were provided by all patients.

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Zhang, F., Bai, H., Gao, R. et al. Dynamics of peripheral T cell clones during PD-1 blockade in non-small cell lung cancer. Cancer Immunol Immunother (2020). https://doi.org/10.1007/s00262-020-02642-4

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Keywords

  • PD-1
  • Cancer immunotherapy
  • Single cell sequencing
  • Non-small cell lung cancer