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

Article Article scientifique Article Functional HPV-specific PD-1+ stem-like CD8 T cells in head and neck cancer eng 2021-09-01 2021-09 author Eberhardt Christiane Sigrid Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA.,Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.,Centre for Vaccinology, University Hospitals Geneva, Geneva, Switzerland.,Division of General Pediatrics, Department of Pediatrics, Gynecology & Obstetrics, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 669023 author Kissick Haydn T 0000-0001-7624-5598 Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA.,Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.,Winship Cancer Institute of Emory University, Atlanta, GA, USA.,Department of Urology, Emory University School of Medicine, Atlanta, GA, USA. author Patel Mihir R Winship Cancer Institute of Emory University, Atlanta, GA, USA.,Department of Otolaryngology, Emory University School of Medicine, Atlanta, GA, USA. author Cardenas Maria A Department of Urology, Emory University School of Medicine, Atlanta, GA, USA. author Prokhnevska Nataliya Department of Urology, Emory University School of Medicine, Atlanta, GA, USA. author Obeng Rebecca C 0000-0001-8624-7108 Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA.,Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.,Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA.,Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. author Nasti Tahseen H Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA.,Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA. author Griffith Christopher C Winship Cancer Institute of Emory University, Atlanta, GA, USA.,Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA. author Im Se Jin Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA.,Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.,Department of Immunology, Sungkyunkwan University School of Medicine, Suwon, South Korea. author Wang Xu Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. author Shin Dongsuk Division of General Pediatrics, Department of Pediatrics, Gynecology & Obstetrics, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. 911731 author Carrington Mary 0000-0002-2692-2180 Basic Science Program, Frederick National Laboratory for Cancer Research in the Laboratory of Integrative Cancer Immunology, National Cancer Institute, Bethesda, MD, USA.,Ragon Institute of MGH, MIT and Harvard, Boston, MA, USA. author Chen Zhuo G Winship Cancer Institute of Emory University, Atlanta, GA, USA.,Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. author Sidney John Division of Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, USA. author Sette Alessandro Division of Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, USA.,Department of Medicine, University of California, San Diego, La Jolla, CA, USA. author Saba Nabil F Winship Cancer Institute of Emory University, Atlanta, GA, USA.,Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. author Wieland Andreas 0000-0001-9648-7922 Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA. andreas.wieland@emory.edu.,Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA. andreas.wieland@emory.edu. author Ahmed Rafi 0000-0002-9591-2621 Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA. rahmed@emory.edu.,Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA. rahmed@emory.edu.,Winship Cancer Institute of Emory University, Atlanta, GA, USA. rahmed@emory.edu. 279-284 10.1038/s41586-021-03862-z 34471285 0028-0836 https://www.nature.com/articles/s41586-021-03862-z 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 Dewey 616.07 Dewey 618 NCATS NIH HHS UL1 TR002378 United States NIH HHS 2P30 CA138292-04 United States NIH HHS P51 OD011132 United States Swiss National Science Foundation Characterization of B cell mediated immunity and longevity to VZV immunization 174483 CH Careers 58 Département de pédiatrie, gynécologie et obstétrique 223 137 Département de pathologie et immunologie 21F false 143 Centre de vaccinologie et d'immunologie néonatale 177 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE180268 Nature 597 7875 48097795-90f3-4c51-bfdd-0252a5016bcb Article (Published version) Restricted 2023_functional.pdf 13702179 application/pdf d3837d42ff1a33a8df1e1f7367a4a936a086ccb63a9be0a80ea954b57cdbe511 e6ac5286-7b4a-4bd2-842d-83436ce0f8e5 Appendix Restricted 41586_2021_3862_MOESM1_ESM.pdf 75441 application/pdf Reporting Summary 8fb6629fefacfbbc1625c911b7da5f346e4785cdd3e109b50b39b39e240f193f 8c08ca4d-340d-494a-adc2-20d7730a6168 Supplemental data Restricted 41586_2021_3862_MOESM2_ESM.xlsx 12413 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Supplementary Table 1: List of reagents. 6b4bde81eea7b35a16377277a01d1361d3377ffa48d2d42ee3cf06f96478b58c 7988982c-535a-4392-8bf7-605ededfb363 Supplemental data Restricted 41586_2021_3862_MOESM3_ESM.xlsx 25459 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Supplementary Table 2: Predicted HPV-peptides used for T cell expansion and epitope mapping. fc74f4366ab78f970de5db83446d8f2de518305a724d1256f00a06ad52accdc1 restrictedAccess Faculté de médecine / Section de médecine clinique / Département de pédiatrie, gynécologie et obstétrique Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie

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Functional HPV-specific PD-1⁺ stem-like CD8 T cells in head and neck cancer	Nature			2021	146	0

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