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Cytokine-armed vaccinia virus promotes cytotoxicity toward pancreatic carcinoma cells via activation of human intermediary CD56(dim)CD16(dim) natural killer cells

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Item Type:Article
Title:Cytokine-armed vaccinia virus promotes cytotoxicity toward pancreatic carcinoma cells via activation of human intermediary CD56(dim)CD16(dim) natural killer cells
Creators Name:Wang, R., Hu, M., Lozzi, I., Jin, C.Z.J., Ma, D., Splith, K., Mengwasser, J., Wolf, V., Feldbrügge, L., Tang, P., Timmermann, L., Hillebrandt, K.H., Kirchner, M., Mertins, P., Hilfenhaus, G., Neumann, C.C.M., Kammertoens, T., Pratschke, J., Malinka, T., Sauer, I.M., Noessner, E., Guo, Z.S. and Felsenstein, M.
Abstract:Pancreatic ductal adenocarcinoma (PDAC) remains a particularly aggressive disease with few effective treatments. The PDAC tumor immune microenvironment (TIME) is known to be immune suppressive. Oncolytic viruses can increase tumor immunogenicity via immunogenic cell death (ICD). We focused on tumor-selective (vvDD) and cytokine-armed Western-reserve vaccinia viruses (vvDD-IL2 and vvDD-IL15) and infected carcinoma cell lines as well as patient-derived primary PDAC cells. In co-culture experiments, we investigated the cytotoxic response and the activation of human natural killer (NK). Infection and virus replication were assessed by measuring virus encoded YFP. We then analyzed intracellular signaling processes and oncolysis via in-depth proteomic analysis, immunoblotting and TUNEL assay. Following the co-culture of mock or virus infected carcinoma cell lines with allogenic PBMCs or NK cell lines, CD56+ NK cells were analyzed with respect to their activation, cytotoxicity and effector function. Both, dose- and time-dependent release of danger signals following infection were measured. Viruses effectively entered PDAC cells, emitted YFP signals and resulted in concomitant oncolysis. The proteome showed reprogramming of normally active core signaling pathways in PDAC (e.g., MAPK-ERK signaling). Danger-associated molecular patterns were released upon infection and stimulated co-cultured NK cells for enhanced effector cytotoxicity. NK cell subtyping revealed enhanced numbers and activation of a rare CD56(dim)CD16(dim) population. Tumor cell killing was primarily triggered via Fas ligands rather than granule release, resulting in marked apoptosis. Overall, the cytokine-armed vaccinia viruses induced NK cell activation and enhanced cytotoxicity toward human PDAC cells in vitro. We could show that cytokine-armed virus targets the carcinoma cells and thus has great potential to modulate the TIME in PDAC.
Keywords:Immune Modulation, Immunogenic Cell Death, Modified Vaccinia Virus, Natural Killer Cells, Proteome Analysis
Source:International Journal of Cancer
ISSN:0020-7136
Publisher:Wiley
Volume:156
Number:3
Page Range:638-651
Date:1 February 2025
Official Publication:https://doi.org/10.1002/ijc.35209
PubMed:View item in PubMed

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