2. Academic Validation
  3. Contrasting interferon-mediated antiviral responses in human lung adenocarcinoma cells

Contrasting interferon-mediated antiviral responses in human lung adenocarcinoma cells

  • J Virol. 2025 Jun 17;99(6):e0046925. doi: 10.1128/jvi.00469-25.
Matthew Esparza # 1,  Sara S El Zahed # 2 3,  Umut Karakus 2 3,  Hanspeter Niederstrasser 4,  Boning Gao 5 6,  Kimberly Batten 1,  Jerry W Shay 1,  Bruce Posner 4,  Fred R Hirsch 7 8 9,  Luc Girard 5 6,  Lily Jun-Shen Huang 1,  John Minna 6 10,  Adolfo García-Sastre 2 3 8 9 11 12,  Beatriz M A Fontoura 1
Affiliations

Affiliations

  • 1 Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  • 2 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • 3 Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • 4 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  • 5 Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  • 6 Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  • 7 Center for Thoracic Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • 8 The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • 9 Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • 10 Departments of Internal Medicine and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  • 11 Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • 12 The Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • # Contributed equally.
PMID: 40434103 DOI: 10.1128/jvi.00469-25
Abstract

Lung cancers develop from lung epithelial cells after a series of genetic and epigenetic changes, and these cells are major sites of Influenza Virus infection. Thus, we explored how changes found in patient-derived lung Cancer cell lines impacted Influenza Virus replication and identified two lines with opposite responses to influenza A viral Infection. We show that the NCI-H820 lung adenocarcinoma (LUAD) is resistant to influenza A virus and VSV Infection, while LUAD line NCI-H322 is highly susceptible to Infection by both viruses. H322 cells have a homozygous deletion in a region of chromosome 9 encoding IFNαgenes, IFNβ1, IFNω1, and IFNε genes, leading to downregulation of immune response and high Infection rates. In contrast, the resistant H820 cell line has three copies of these same interferon genes and shows increased expression of interferon-regulated genes. We found that the resistance of H820 cells to influenza Infection is likely linked to impaired viral entry-due to high basal levels of interferon-induced proteins known to inhibit endocytosis (IFITM1/2/3, NCOA7, and CH25H)-and to increased expression of mRNAs that encode other Antiviral factors. In contrast, H322 cells show the absence or low levels of interferon-regulated genes involved in the inhibition of viral entry. These results suggest that the opposite phenotypes on viral entry of H322 and H820 cells may be at least in part associated with impaired or enhanced interferon response, respectively. Since most lung Cancer patients have genomic characterization of their tumors, individualized differences in interferon responses may have therapeutic and patient management implications.

Importance: Lung cancers develop from genetic and epigenetic changes that can dramatically influence patients' susceptibility to viral Infection and replication. This study evaluates the responses to Influenza Virus infection of two patient-derived lung Cancer cell lines. Interestingly, the cell lines investigated are of the same Cancer type, lung adenocarcinomas, yet one cell line is highly susceptible, while the Other cell line is highly resistant to viral Infection. This is in part due to contrasting genetic alterations that lead to changes in the interferon response pathways, which differentially impact viral entry. Thus, identifying these risk factors can inform the prognosis of patients infected with Influenza Virus and guide their personalized treatment plans.

Keywords

influenza; interferons; lung cancer; viral entry.

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