Type I interferon drives a cellular state inert to TCR-stimulation and could impede effective T-cell differentiation in cancer
Dillon Corvino1*, Martin Batstone2,3, Brett G.M Hughes2,3, Tim Kempchen1, Susanna S. Ng1, Nazhifah Salim1, Franziska Schneppenheim1, Denise Rommel1, Ananthi Kumar1, Sally Pearson4, Jason Madore4, Lambross T. Koufariotis4, Lisa Maria Steinheuer1, Dilan Pathirana5, Kevin Thurley1, Michael Hölzel1, Nicholas Borcherding6, Matthias Braun7#, and Tobias Bald1*#
1 Tumor-Immunobiology, Institute for Experimental Oncology, University Hospital Bonn, Bonn, Germany
2 Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
3 Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia
4 QIMR Berghofer Medical Research Institute, Herston, Australia
5 Faculty of Mathematics and Natural Sciences, and the Life and Medical Sciences Institute (LIMES), Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
6 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
7 Department of Paediatric Haematology, Oncology and Immunodeficiency, Justus-Liebig-University Giessen, Giessen, Germany
# Shared senior authorship
* Correspondence
Correspondence:
Dillon Corvino, Institute for Experimental Oncology, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany
Corvino.Dillon@ukbonn.de
Tobias Bald, Institute for Experimental Oncology, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany
Tobias.Bald@ukbonn.de
Background: Head and neck squamous cell carcinoma (HNSCC) is linked to human papillomavirus (HPV) infection. HPV-positive and HPV-negative HNSCC exhibit distinct molecular and clinical characteristics. Although checkpoint inhibitors have shown efficiency in recurrent/metastatic HNSCC, response variability persists regardless of HPV status. This study aimed to explore the CD8+ T-cell landscape in HPV-negative HNSCC.
Methods: We performed simultaneous single-cell RNA and TCR sequencing of CD8+ tumor-infiltrating lymphocytes (TILs) from treatment-naïve HPV-negative HNSCC patients. Additionally, cells were stimulated ex vivo, which allowed for the tracking of clonal transcriptomic responses.
Results: Our analysis identified a subset of CD8+ TILs highly enriched for interferon-stimulated genes (ISG). TCR analysis revealed ISG cells are clonally related to a population of granzyme K (GZMK)-expressing cells. However, unlike GZMK cells, which exhibited rapid effector-like phenotypes following stimulation, ISG cells were transcriptionally inert. Additionally, ISG cells showed specific enrichment within tumor and were found across multiple tumor entities.
Conclusions: ISG-enriched CD8+ TILs are a consistent feature of various tumor entities. These cells are poorly understood but possess characteristics which may impact anti-tumor immunity. Understanding the unique properties and functionality of ISG cells could offer innovative treatment approaches to improve patient outcomes in HPV-negative HNSCC and other cancer types.
This code and analysis were authored by Dillon Corvino.