Scientific article

Functional HPV-specific PD-1+ stem-like CD8 T cells in head and neck cancer

Published inNature, vol. 597, no. 7875, p. 279-284
Publication date2021-09
First online date2021-09-01

T cells are important in tumour immunity but a better understanding is needed of the differentiation of antigen-specific T cells in human cancer1,2. Here we studied CD8 T cells in patients with human papillomavirus (HPV)-positive head and neck cancer and identified several epitopes derived from HPV E2, E5 and E6 proteins that allowed us to analyse virus-specific CD8 T cells using major histocompatibility complex (MHC) class I tetramers. HPV-specific CD8 T cells expressed PD-1 and were detectable in the tumour at levels that ranged from 0.1% to 10% of tumour-infiltrating CD8 T lymphocytes (TILs) for a given epitope. Single-cell RNA-sequencing analyses of tetramer-sorted HPV-specific PD-1+CD8 TILs revealed three transcriptionally distinct subsets. One subset expressed TCF7 and other genes associated with PD-1+stem-like CD8 T cells that are critical for maintaining T cell responses in conditions of antigen persistence. The second subset expressed more effector molecules, representing a transitory cell population, and the third subset was characterized by a terminally differentiated gene signature. T cell receptor clonotypes were shared between the three subsets and pseudotime analysis suggested a hypothetical differentiation trajectory from stem-like to transitory to terminally differentiated cells. More notably, HPV-specific PD-1+TCF-1+stem-like TILs proliferated and differentiated into more effector-like cells after in vitro stimulation with the cognate HPV peptide, whereas the more terminally differentiated cells did not proliferate. The presence of functional HPV-specific PD-1+TCF-1+CD45RO+stem-like CD8 T cells with proliferative capacity shows that the cellular machinery to respond to PD-1 blockade exists in HPV-positive head and neck cancer, supporting the further investigation of PD-1 targeted therapies in this malignancy. Furthermore, HPV therapeutic vaccination efforts have focused on E6 and E7 proteins; our results suggest that E2 and E5 should also be considered for inclusion as vaccine antigens to elicit tumour-reactive CD8 T cell responses of maximal breadth.

  • Alphapapillomavirus / immunology
  • Alphapapillomavirus / isolation & purification
  • CD8-Positive T-Lymphocytes / classification
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cancer Vaccines / immunology
  • Cell Differentiation
  • Cell Proliferation
  • DNA-Binding Proteins / immunology
  • Head and Neck Neoplasms / immunology
  • Head and Neck Neoplasms / virology
  • Humans
  • Lymphocytes, Tumor-Infiltrating / classification
  • Lymphocytes, Tumor-Infiltrating / cytology
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Oncogene Proteins, Viral / immunology
  • Papillomavirus Infections / immunology
  • Papillomavirus Infections / virology
  • Papillomavirus Vaccines / immunology
  • Programmed Cell Death 1 Receptor / metabolism
  • RNA-Seq
  • Receptors, Antigen, T-Cell / immunology
  • Single-Cell Analysis
  • Stem Cells / cytology
  • Stem Cells / immunology
  • T Cell Transcription Factor 1 / metabolism
  • T-Lymphocytes / immunology
  • Transcription, Genetic
Citation (ISO format)
EBERHARDT, Christiane Sigrid et al. Functional HPV-specific PD-1<sup>+</sup> stem-like CD8 T cells in head and neck cancer. In: Nature, 2021, vol. 597, n° 7875, p. 279–284. doi: 10.1038/s41586-021-03862-z
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Article (Published version)
Secondary files (3)
ISSN of the journal0028-0836

Technical informations

Creation08/29/2022 2:22:08 PM
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Update time05/05/2023 10:06:09 AM
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