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Combination of IAP Antagonists and TNF-?-Armed Oncolytic Viruses Induce Tumor Vascular Shutdown and Tumor Regression.

ABSTRACT: Smac mimetic compounds (SMCs) are anti-cancer drugs that antagonize Inhibitor of Apoptosis proteins, which consequently sensitize cancer cells to death in the presence of proinflammatory ligands such as tumor necrosis factor alpha (TNF-?). SMCs synergize with the attenuated oncolytic vesicular stomatitis virus (VSV?51) by eliciting an innate immune response, which is dependent on the endogenous production of TNF-? and type I interferon. To improve on this SMC-mediated synergistic response, we generated TNF-?-armed VSV?51 to produce elevated levels of this death ligand. Due to ectopic expression of TNF-? from infected cells, a lower viral dose of TNF-?-armed VSV?51 combined with treatment of the SMC LCL161 was sufficient to improve the survival rate compared to LCL161 and unarmed VSV?51 co-therapy. This improved response is attributed to a bystander effect whereby the spread of TNF-? from infected cells leads to the death of uninfected cells in the presence of LCL161. In addition, the treatments induced vascular collapse in solid tumors with a concomitant increase of tumor cell death, revealing another mechanism by which cytokine-armed VSV?51 in combination with LCL161 can kill tumor cells. Our studies demonstrate the potential for cytokine-engineered oncolytic virus and SMCs as a new combination immunotherapy for cancer treatment.

SUBMITTER: Beug ST

PROVIDER: S-EPMC6076221 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Combination of IAP Antagonists and TNF-α-Armed Oncolytic Viruses Induce Tumor Vascular Shutdown and Tumor Regression.

Beug Shawn T ST Pichette Stephanie J SJ St-Jean Martine M Holbrook Janelle J Walker Danielle E DE LaCasse Eric C EC Korneluk Robert G RG

Molecular therapy oncolytics 20180621

Smac mimetic compounds (SMCs) are anti-cancer drugs that antagonize Inhibitor of Apoptosis proteins, which consequently sensitize cancer cells to death in the presence of proinflammatory ligands such as tumor necrosis factor alpha (TNF-α). SMCs synergize with the attenuated oncolytic vesicular stomatitis virus (VSVΔ51) by eliciting an innate immune response, which is dependent on the endogenous production of TNF-α and type I interferon. To improve on this SMC-mediated synergistic response, we ge ...[more]

PMID: 30101187

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Project description:ObjectiveIn this work, we examine the molecular basis for capillary tube regression and identify key proregressive factors, signaling pathways, and pharmacological antagonists of this process. Approach and Results: We demonstrate that the proinflammatory mediators, IL (interleukin)-1β, TNF (tumor necrosis factor) α, and thrombin, singly and in combination, are potent regulators of capillary tube regression in vitro. These proregressive factors, when added to endothelial cell-pericyte cocultures, led to selective loss of endothelial cell-lined tube networks, with retention and proliferation of pericytes despite the marked destruction of adjacent capillary tubes. Moreover, treatment of macrophages with the TLR (toll-like receptor) agonists Pam3CSK4 and lipopolysaccharide generates conditioned media with marked proregressive activity, that is completely blocked by a combination of neutralizing antibodies directed to IL-1β and TNFα but not to other factors. The same combination of blocking antibodies, as well as the anti-inflammatory cytokine IL-10, interfere with macrophage-dependent hyaloid vasculature regression in mice suggesting that proinflammatory cytokine signaling regulates capillary regression in vivo. In addition, we identified a capillary regression signaling signature in endothelial cells downstream of these proregressive agents that is characterized by increased levels of ICAM-1 (intercellular adhesion molecule-1), phospho-p38, and phospho-MLC2 (myosin light chain-2) and decreased levels of phospho-Pak2, acetylated tubulin, phospho-cofilin, and pro-caspase3. Finally, we identified combinations of pharmacological agents (ie, FIST and FISTSB) that markedly rescue the proregressive activities of IL-1β, TNFα, and thrombin, individually and in combination.ConclusionsOverall, these new studies demonstrate that the major proinflammatory mediators, IL-1β, TNFα, and thrombin, are key regulators of capillary tube regression-a critical pathological process regulating human disease.

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Combination of IAP Antagonists and TNF-?-Armed Oncolytic Viruses Induce Tumor Vascular Shutdown and Tumor Regression.

Publications

Combination of IAP Antagonists and TNF-α-Armed Oncolytic Viruses Induce Tumor Vascular Shutdown and Tumor Regression.

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