Interplay between oncolytic measles virus, macrophages and cancer cells induces a proinflammatory tumor...

Area of Science:

• Oncology
• Virology
• Immunology

Background:

• Attenuated measles virus (MV) has oncolytic activity against malignant pleural mesothelioma (MPM) cells, particularly those deficient in type-I interferon (IFN-I) pathways.
• Myeloid cells within the tumor microenvironment (TME) possess functional antiviral responses that can influence oncolytic virotherapy efficacy.

Purpose of the Study:

• To investigate the interaction between MV and myeloid cells (monocytes and macrophages) in human MPM.
• To understand how myeloid cells affect MV oncolytic activity and the tumor microenvironment in MPM.

Main Methods:

• Co-culture of MPM cell lines with human monocytes or macrophages, followed by MV infection.
• Transcriptome analysis, high-dimensional flow cytometry for phenotype and secretion analysis, and measurement of transgene expression (GFP) from MV.
• Assessment of IFN-I signaling pathway modulation by ruxolitinib.

Main Results:

• MPM cells promote monocyte differentiation into M2-like macrophages.
• These macrophages inhibit MV transgene expression in MPM cells with defective IFN-I production but intact signaling, while having less impact on cells unresponsive to IFN-I.
• MV infection induces antiviral and pro-inflammatory gene expression in macrophages, enhances their phagocytic activity, and upregulates HLA and costimulatory molecules.
• MV infection increases secretion of inflammatory cytokines, including IFN-I, and PD-L1 expression in both tumor cells and macrophages.

Conclusions:

• Myeloid-derived macrophages can limit MV protein expression in certain MPM subtypes via IFN-I production.
• The interplay between MV and macrophages creates a pro-inflammatory environment that may enhance the anti-tumor immune response in MPM.
• Targeting myeloid cell interactions could be a strategy to optimize MV-based oncolytic virotherapy for MPM.