ORCID

0009-0009-6705-3872

Keywords

Oncolytic virus; parainfluenza virus type 5; natural killer cells; cancer immunotherapeutic; interferon-gamma; interferon-alpha/beta

Abstract

Type I interferon (IFN-I) and interferon-gamma (IFN-γ) are potent cytokines that can be produced by virus-infected cells and Natural Killer (NK) cells, respectively. The relative roles of these two IFNs in promoting NK cell killing of tumor cells was tested in the context of combining particle-based ex vivo expanded PM21-NK cells and infection with oncolytic Parainfluenza virus 5 (PIV5). Activated NK cells produce IFN-γ, which can upregulate NK cell inhibitory ligands on tumor cells and reduce NK cell killing. We hypothesized that resistance of tumor cells to NK cell killing could be overcome by expression of the PIV5 V protein, which has known roles in blocking IFN-γ signaling. Delivery of V protein to neuroblastoma cells conferred resistance to IFN-γ-mediated increases in NK cell inhibitory ligands and increased susceptibility to PM21-NK cell-mediated killing. We used a PIV5 P/V gene mutant that is a strong inducer of IFN-I synthesis and WT PIV5 which is a poor inducer of IFN-I to test the hypothesis that IFN-I positively mediates NK cell functions. Both WT and P/V mutant viruses infected PM21-NK cells and caused extensive cytopathic effects. In a co-culture model, WT PIV5 was able to spread to naïve NK cells but IFN-I induction by the P/V mutant protected NK cells from virus spread. Direct treatment of PM21-NK cells with IFN-I: 1) enhanced NK cell cytotoxicity towards tumor cells, due in-part to upregulation of the death ligand TRAIL, and 2) also reduced IFN-γ secretion. Our results uncover opposing effects of IFN-I and IFN-γ on NK cell killing of tumor cells in culture, with IFN-I promoting PM21-NK cell killing by multiple mechanisms. Our findings provide a foundation for exploiting properties of PIV5 oncolytic viruses (e.g., V protein, IFN-I induction) to promote their therapeutic use along with adoptively transferred NK cells.

Completion Date

2025

Semester

Summer

Committee Chair

Parks, Griffith

Degree

Doctor of Philosophy (Ph.D.)

College

College of Medicine

Format

PDF

Identifier

DP0029613

Language

English

Document Type

Thesis

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