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Tumor-targeting and cytokine-armed vaccinia virus promotes cytotoxicity towards pancreatic carcinoma cells via activation of human intermediary CD56dimCD16dim natural killer cells.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains a particularly aggressive disease with few effective treatments. The PDAC tumor immune microenvironment (TIME) has been characterized as immune suppressed. Oncolytic viruses can increase tumor antigenicity via immunogenic cell death (ICD). In this study, tumor-targeting and cytokine-armed vaccinia viruses (vvDD, vvDD-IL2, vvDD-IL15) were used to infect carcinoma cell lines as well as patient-derived primary PDAC cells. In co-culture experiments we tested the cytotoxic response and the activation of human natural killer-(NK-)cells during the oncolytic process.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Pancreatic Cancer

SUBMITTER: Marieluise Kirchner

LAB HEAD: Philipp Mertins

PROVIDER: PXD048276 | Pride | 2024-09-20

REPOSITORIES: pride

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			Action	DRS
	Leia_20210212_SN_HStmtpro_Feist_glob_01.raw	Raw
	Leia_20210212_SN_HStmtpro_Feist_glob_02.raw	Raw
	Leia_20210212_SN_HStmtpro_Feist_glob_03.raw	Raw
	Leia_20210212_SN_HStmtpro_Feist_glob_04.raw	Raw
	Leia_20210212_SN_HStmtpro_Feist_glob_05.raw	Raw

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Project description:Previously we reported that a recombinant vaccinia virus (VACV) carrying a light-emitting fusion gene enters, replicates in, and reveals the locations of tumors in mice. A new recombinant VACV, GLV-1h68, as a simultaneous diagnostic and therapeutic agent, was constructed by inserting three expression cassettes (encoding Renilla luciferase-green fluorescent protein (RUC-GFP) fusion, b-galactosidase, and b-glucuronidase) into the F14.5L, J2R (encoding thymidine kinase, TK), and A56R (encoding hemagglutinin, HA) loci of the viral genome, respectively. Intravenous (i.v.) injections of GLV-1h68 (1 Ã 107 pfu/mouse) into nude mice with established (500 mm3) subcutaneous (s.c.) GI-101A human breast tumors were used to evaluate its toxicity, tumor targeting specificity and oncolytic efficacy. GLV-1h68 demonstrated an enhanced tumor targeting specificity and much reduced toxicity compared to its parental LIVP strains. The tumors colonized by GLV-1h68 exhibited growth, inhibition, and regression phases followed by tumor eradication within 130 days in 95% of the mice tested. Tumor regression in live animals was monitored in real time based on decreasing light emission, hence demonstrating the concept of a combined oncolytic virus-mediated tumor diagnosis and therapy system. Transcriptional profiling of regressing tumors based on a mouse-specific platform revealed gene expression signatures consistent with immune defense activation, inclusive of interferon stimulated genes (STAT-1 and IRF-7), cytokines, chemokines and innate immune effector function. These findings suggest that immune activation may combine with viral oncolysis to induce tumor eradication in this model, providing a novel perspective for the design of oncolytic viral therapies for human cancers. Objective: To determine the gene expression changes induced by GLV-1h68 vaccinia virus injection in mouse carrying human breast cancer implant and leading to tumor eradication. Methods: Gene expression was analyzed using oligonucleotide microarrays. Responsiveness to vaccina virus injection was assessed by toxicity and survival study, gene expression anaysis and tumor volume change. Result: The tumors colonized by GLV-1h68 exhibited growth, inhibition, and regression phases followed by tumor eradication within 130 days in 95% of the mice tested. Tumor regression in live animals was monitored in real time based on decreasing light emission, hence demonstrating the concept of a combined oncolytic virus-mediated tumor diagnosis and therapy system. Transcriptional profiling of regressing tumors based on a mouse-specific platform revealed gene expression signatures consistent with immune defense activation, inclusive of interferon stimulated genes (STAT-1 and IRF-7), cytokines, chemokines and innate immune effector function. Conclusion: Our findings suggest that immune activation may combine with viral oncolysis to induce tumor eradication in this model, providing a novel perspective for the design of oncolytic viral therapies for human cancers. Experiment Overall Design: tumor tissues 3 and 6 weeks post virus injection

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Tumor-targeting and cytokine-armed vaccinia virus promotes cytotoxicity towards pancreatic carcinoma cells via activation of human intermediary CD56dimCD16dim natural killer cells.

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