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Peer-reviewedCC BY 4.0Cancers

Tumour Cell-Associated Heterogeneity in Antiviral Immunity Shapes Influenza Responses and Immune-Modulatory Signalling in Lung Cancer

  • Mark A. Miles1
  • Isabella Rosano1
  • Stella Liong1
  • Jessica M. Logan2
  • John J. O’Leary3,4,5
  • Doug A. Brooks2,3
  • Stavros Selemidis1
5 affiliations
  1. 1Centre for Respiratory Science and Health, School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia
  2. 2School of Pharmacy and Biomedical Science, College of Health, Adelaide University, North Terrace, Adelaide, SA 5001, Australia
  3. 3Discipline of Histopathology, School of Medicine, Trinity Translational Medicine Institute (TTMI), Trinity College Dublin, XW7X Dublin, Ireland
  4. 4Sir Patrick Dun’s Laboratory, Central Pathology Laboratory, St James’s Hospital, XW7X Dublin, Ireland
  5. 5CERVIVA Research Consortium, Trinity College Dublin, XW7X Dublin, Ireland
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Abstract

Background/Objectives: Respiratory viral infections occur within the same anatomical niche as lung cancer, yet how lung cancer cells respond to infection and how these responses influence antiviral and inflammatory signalling remain poorly understood. This study investigated innate immune responses to influenza A virus (IAV) infection across a panel of lung epithelial cell lines. Methods: Non-malignant bronchial epithelial and non-small cell lung cancer (NSCLC) cell lines representing adenocarcinoma and squamous cell carcinoma were infected with IAV. Antiviral and inflammatory gene expression, viral RNA and protein detection, infection-induced cell death, pattern recognition receptor expression, and immune checkpoint ligand expression were assessed using molecular, biochemical and flow cytometric approaches. Interferon (IFN) receptor blockade and mitochondrial reactive oxygen species scavenging were used to investigate selected signalling mechanisms. Results: NSCLC cell lines exhibited heterogeneous innate immune responses to IAV infection, with differential regulation of RNA-sensing pathways and canonical antiviral signalling components. Although IFN responses were retained, NSCLC cells exhibited reduced infection-induced apoptosis and prolonged viral RNA and protein detection compared with non-malignant epithelial cells. IAV infection was also associated with changes in DNA-sensing receptor expression, including TLR9, and increased expression of the immune checkpoint ligand PD-L1. Conclusions: These findings identify substantial cell line-associated heterogeneity in antiviral responses to IAV across lung epithelial cell lines, including NSCLC cells. The observed differences in viral RNA and protein detection, cell death responses and immune-modulatory signalling provide a framework for understanding how respiratory viral infections may interact with lung cancer cells to shape antiviral and inflammatory responses within the tumour environment.

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Cite

BibTeXRIS
BibTeX
@article{miles2026tumour,
  title = {{Tumour Cell-Associated Heterogeneity in Antiviral Immunity Shapes Influenza Responses and Immune-Modulatory Signalling in Lung Cancer}},
  author = {Mark A. Miles and Isabella Rosano and Stella Liong and Jessica M. Logan and John J. O’Leary and Doug A. Brooks and Stavros Selemidis},
  journal = {Cancers},
  year = {2026},
  month = oct,
  doi = {10.3390/cancers18213502},
  url = {https://www.mdpi.com/2072-6694/18/21/3502},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Tumour Cell-Associated Heterogeneity in Antiviral Immunity Shapes Influenza Responses and Immune-Modulatory Signalling in Lung Cancer
AU  - Mark A. Miles
AU  - Isabella Rosano
AU  - Stella Liong
AU  - Jessica M. Logan
AU  - John J. O’Leary
AU  - Doug A. Brooks
AU  - Stavros Selemidis
PY  - 2026
DA  - 2026/10/30
JO  - Cancers
DO  - 10.3390/cancers18213502
UR  - https://www.mdpi.com/2072-6694/18/21/3502
AB  - Background/Objectives: Respiratory viral infections occur within the same anatomical niche as lung cancer, yet how lung cancer cells respond to infection and how these responses influence antiviral and inflammatory signalling remain poorly understood. This study investigated innate immune responses to influenza A virus (IAV) infection across a panel of lung epithelial cell lines. Methods: Non-malignant bronchial epithelial and non-small cell lung cancer (NSCLC) cell lines representing adenocarcinoma and squamous cell carcinoma were infected with IAV. Antiviral and inflammatory gene expression, viral RNA and protein detection, infection-induced cell death, pattern recognition receptor expression, and immune checkpoint ligand expression were assessed using molecular, biochemical and flow cytometric approaches. Interferon (IFN) receptor blockade and mitochondrial reactive oxygen species scavenging were used to investigate selected signalling mechanisms. Results: NSCLC cell lines exhibited heterogeneous innate immune responses to IAV infection, with differential regulation of RNA-sensing pathways and canonical antiviral signalling components. Although IFN responses were retained, NSCLC cells exhibited reduced infection-induced apoptosis and prolonged viral RNA and protein detection compared with non-malignant epithelial cells. IAV infection was also associated with changes in DNA-sensing receptor expression, including TLR9, and increased expression of the immune checkpoint ligand PD-L1. Conclusions: These findings identify substantial cell line-associated heterogeneity in antiviral responses to IAV across lung epithelial cell lines, including NSCLC cells. The observed differences in viral RNA and protein detection, cell death responses and immune-modulatory signalling provide a framework for understanding how respiratory viral infections may interact with lung cancer cells to shape antiviral and inflammatory responses within the tumour environment.
SN  - 2072-6694
ER  -