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

Christiane S. Eberhardt, Haydn T. Kissick, Mihir R. Patel, Maria A. Cardenas, Nataliya Prokhnevska, Rebecca C. Obeng, Tahseen H. Nasti, Christopher C. Griffith, Se Jin Im, Xu Wang, Dong M. Shin, Mary Carrington, Zhuo G. Chen, John Sidney, Alessandro Sette, Nabil F. Saba, Andreas Wieland () and Rafi Ahmed ()
Additional contact information
Christiane S. Eberhardt: Emory University School of Medicine
Haydn T. Kissick: Emory University School of Medicine
Mihir R. Patel: Winship Cancer Institute of Emory University
Maria A. Cardenas: Emory University School of Medicine
Nataliya Prokhnevska: Emory University School of Medicine
Rebecca C. Obeng: Emory University School of Medicine
Tahseen H. Nasti: Emory University School of Medicine
Christopher C. Griffith: Winship Cancer Institute of Emory University
Se Jin Im: Emory University School of Medicine
Xu Wang: Emory University School of Medicine
Dong M. Shin: University of Geneva
Mary Carrington: National Cancer Institute
Zhuo G. Chen: Winship Cancer Institute of Emory University
John Sidney: Division of Vaccine Discovery, La Jolla Institute for Immunology
Alessandro Sette: Division of Vaccine Discovery, La Jolla Institute for Immunology
Nabil F. Saba: Winship Cancer Institute of Emory University
Andreas Wieland: Emory University School of Medicine
Rafi Ahmed: Emory University School of Medicine

Nature, 2021, vol. 597, issue 7875, 279-284

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41586-021-03862-z

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