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Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
Replication-incompetent influenza A viruses armed with IFN-γ effectively mediate immune modulation and tumor
Ramona Meissner1,2,3, Viktor Wixler1, Franziska Paulina Wulfert1
1Institute of Molecular Virology, Centre for Molecular Biology of Inflammation, Westfaelische Wilhelms University of Münster, 48149 Münster, Germany.
Abstract:
Low pathogenic influenza A viruses (IAVs) have shown promising oncolytic potential in lung cancer-bearing mice. However, as replication-competent pathogens, they may cause side effects in immunocompromised cancer patients. To circumvent this problem, we genetically engineered nonreplicating IAVs lacking the hemagglutinin (HA) gene (ΔHA IAVs), but reconstituted the viral envelope with recombinant HA proteins to allow a single infection cycle. To optimize the therapeutic potential and improve immunomodulatory properties, these replication-incompetent IAVs were complemented with a murine interferon-gamma (mIFN-γ) gene. After intratracheal administration to transgenic mice that develop non-small cell lung cancer (NSCLC), the ΔHA IAVs induced potent tumor destruction. However, ΔHA IAVs armed with mIFN-γ exhibited an even stronger and more sustained effect, achieving 85% tumor reduction at day 12 postinfection. In addition, ΔHA-mIFN-γ viruses were proven to be efficient in recruiting and activating natural killer cells and macrophages from the periphery and in inducing cytotoxic T lymphocytes. Most important, both viruses, and particularly IFN-γ-encoding viruses, activated tumor-associated alveolar macrophages toward a proinflammatory M1-like phenotype. Therefore, replication-incompetent ΔHA-mIFN-γ-IAVs are safe and efficient oncolytic viruses that additionally exhibit immune cell activating properties and thus represent a promising innovative therapeutic option in the fight against NSCLC.
Insights
Genetically engineered nonreplicating influenza A viruses (IAVs) show promise as oncolytic therapy for non-small cell lung cancer (NSCLC). These modified IAVs, especially when armed with interferon-gamma (IFN-γ), effectively reduce tumors and activate anti-cancer immune cells.
Area of Science:
- Oncology
- Virology
- Immunotherapy
Background:
- Low pathogenic influenza A viruses (IAVs) demonstrate oncolytic potential in preclinical lung cancer models.
- Replication-competent IAVs pose safety concerns for immunocompromised cancer patients.
- Genetic engineering offers a strategy to create safer, targeted oncolytic viral therapies.
Purpose of the Study:
- To develop replication-incompetent IAVs (ΔHA IAVs) for enhanced safety in oncolytic virotherapy.
- To augment the therapeutic efficacy and immunomodulatory properties of ΔHA IAVs by incorporating a murine interferon-gamma (mIFN-γ) gene.
- To evaluate the safety and efficacy of ΔHA-mIFN-γ IAVs in a preclinical non-small cell lung cancer (NSCLC) model.
Main Methods:
- Generation of replication-incompetent influenza A viruses (ΔHA IAVs) lacking the hemagglutinin (HA) gene, complemented with recombinant HA.
- Engineering of ΔHA IAVs to express a murine interferon-gamma (mIFN-γ) gene.
- Intratracheal administration of engineered IAVs to transgenic mice with induced non-small cell lung cancer (NSCLC).
- Assessment of tumor reduction, immune cell recruitment and activation (NK cells, macrophages, CTLs), and macrophage phenotype modulation.
Main Results:
- Intratracheal administration of ΔHA IAVs induced significant tumor destruction in NSCLC-bearing mice.
- ΔHA IAVs engineered with mIFN-γ (ΔHA-mIFN-γ) demonstrated superior and sustained tumor reduction (85% at day 12).
- ΔHA-mIFN-γ viruses effectively recruited and activated natural killer cells, macrophages, and induced cytotoxic T lymphocytes.
- Both virus types, particularly ΔHA-mIFN-γ, promoted a proinflammatory M1-like phenotype in tumor-associated alveolar macrophages.
Conclusions:
- Replication-incompetent ΔHA-mIFN-γ-IAVs are safe and effective oncolytic agents for NSCLC.
- These engineered IAVs possess potent immune-activating properties, enhancing their therapeutic potential.
- ΔHA-mIFN-γ IAVs represent a promising innovative therapeutic strategy for non-small cell lung cancer.
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