A Type I IFN-Inducing Oncolytic Virus Improves NK Cell-Mediated Killing of Tumor Cells In Vitro Through Multiple...

Area of Science:

• Immunology
• Virology
• Cancer Therapy

Background:

• Natural killer (NK) cells and oncolytic viruses are individually effective cancer therapies.
• Combining NK cells with oncolytic viruses can improve tumor cell lysis.
• Understanding how virus-host interactions modulate NK cell activity is crucial for optimizing combination therapies.

Purpose of the Study:

• To investigate how different strains of parainfluenza virus 5 (PIV5) affect NK cell activity in the context of cancer therapy.
• To compare the impact of a wild-type (WT) PIV5 and a P/V gene mutant PIV5 on human NK cells (PM21-NK cells) when tumor cells are infected.

Main Methods:

• In vitro co-culture experiments using expanded human NK cells (PM21-NK cells) and tumor cells infected with either WT PIV5 or a P/V mutant PIV5.
• Assessment of NK cell infection, viral spread, and modulation of NK cell activities, including cytotoxicity and cytokine secretion.
• Analysis of the role of type 1 interferon (IFN-I) in mediating NK cell responses.

Main Results:

• Both WT and P/V mutant PIV5 infected PM21-NK cells and caused cytopathic effects.
• WT PIV5 spread to naive NK cells, whereas the P/V mutant's spread was inhibited by IFN-I induction.
• IFN-I treatment, or media from P/V mutant-infected tumor cells, enhanced NK cell cytotoxicity, partly via TRAIL upregulation.
• IFN-I treatment decreased IFN-γ secretion from PM21-NK cells.

Conclusions:

• Oncolytic viruses that induce type 1 interferon (IFN-I) can significantly enhance NK cell-mediated tumor killing.
• IFN-I upregulates NK cell cytotoxicity and downregulates inhibitory cytokines like IFN-γ.
• This study highlights mechanisms by which IFN-I-inducing oncolytic viruses improve NK cell immunotherapy efficacy against infected and uninfected tumor cells.