TY - JOUR
T1 - Type I Interferon Drives a Cellular State Inert to TCR-Stimulation and Could Impede Effective T-Cell Differentiation in Cancer
AU - Corvino, Dillon
AU - Batstone, Martin
AU - Hughes, Brett G.M.
AU - Kempchen, Tim
AU - Ng, Susanna S.
AU - Salim, Nazhifah
AU - Schneppenheim, Franziska
AU - Rommel, Denise
AU - Kumar, Ananthi
AU - Pearson, Sally
AU - Madore, Jason
AU - Koufariotis, Lambross T.
AU - Steinheuer, Lisa Maria
AU - Pathirana, Dilan
AU - Thurley, Kevin
AU - Hölzel, Michael
AU - Borcherding, Nicholas
AU - Braun, Matthias
AU - Bald, Tobias
N1 - Publisher Copyright:
© 2024 The Author(s). European Journal of Immunology published by Wiley-VCH GmbH.
PY - 2025/1
Y1 - 2025/1
N2 - 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 that may impact antitumor 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.
AB - 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 that may impact antitumor 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.
KW - CD8 T-cells
KW - HNSCC TILs
KW - Type I IFN
KW - scRNAseq
KW - scTCRseq
UR - http://www.scopus.com/inward/record.url?scp=85208785848&partnerID=8YFLogxK
U2 - 10.1002/eji.202451371
DO - 10.1002/eji.202451371
M3 - Article
AN - SCOPUS:85208785848
SN - 0014-2980
VL - 55
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 1
M1 - e202451371
ER -