Selective replication of oncolytic virus M1 results in a bystander killing effect that is potentiated by Smac mimetics

Abstract

Oncolytic virotherapy is a treatment modality that uses native or genetically modified viruses that selectively replicate in and kill tumor cells. Viruses represent a type of pathogen-associated molecular pattern and thereby induce the up-regulation of dozens of cytokines via activating the host innate immune system. Second mitochondria-derived activator of caspases (Smac) mimetic compounds (SMCs), which antagonize the function of inhibitor of apoptosis proteins (IAPs) and induce apoptosis, sensitize tumor cells to multiple cytokines. Therefore, we sought to determine whether SMCs sensitize tumor cells to cytokines induced by the oncolytic M1 virus, thus enhancing a bystander killing effect. Here, we report that SMCs potentiate the oncolytic effect of M1 in vitro, in vivo, and ex vivo. This strengthened oncolytic efficacy resulted from the enhanced bystander killing effect caused by the M1 virus via cytokine induction. Through a microarray analysis and subsequent validation using recombinant cytokines, we identified IL-8, IL-1A, and TRAIL as the key cytokines in the bystander killing effect. Furthermore, SMCs increased the replication of M1, and the accumulation of virus protein induced irreversible endoplasmic reticulum stress-and c-Jun N-terminal kinase-mediated apoptosis. Nevertheless, the combined treatment with M1 and SMCs had little effect on normal and human primary cells. Because SMCs selectively and significantly enhance the bystander killing effect and the replication of oncolytic virus M1 specifically in cancer cells, this combined treatment may represent a promising therapeutic strategy.oncolytic virus | SMAC mimetics | bystander killing effect

Targeting triple-negative breast cancers with the Smac-mimetic birinapant

“…The efficacy of Smac mimetics relies on sufficient quantities of TNF, which can be augmented by other means, including innate immune stimuli [47][48][49], p38, MK2, or caspase inhibitors [37,50]. Although high levels of TNF can be a concern in regard to safety, these combinations have been proven to be well-tolerated in mice [37,47,49,50].…”

Intravenous injection of the oncolytic virus M1 awakens antitumor T cells and overcomes resistance to checkpoint blockade

“…In 2014, our team identified M1, a strain of alphavirus isolated from culicine mosquitoes in the Hainan Province of China, as a novel OV capable of inducing endoplasmic reticulum (ER) stress-mediated apoptosis in zinc-finger antiviral protein-deficient cancer cells 25,26 . A series of small-molecule synergists have been found to magnify viral replication-mediated killing in vitro (cell lines), ex vivo (human tumor tissues), and in vivo (T celldeficient nude mice) [27][28][29][30] . Relevant studies have shown that potent T-cell responses are required for the marked efficacy of cancer immunotherapy 9,11 ; hence, T cells, especially cytotoxic CD8 + T cells, are probably critical to the efficacy of M1, although these cells may also mediate rapid viral elimination.…”

Overexpression of Smac by an Armed Vesicular Stomatitis Virus Overcomes Tumor Resistance

“…Smac mimetics have been shown to sensitize tumor cells to OVs and other anticancer agents 9, 10, 11. Oncolytic adenoviruses and vaccinia virus armed with Smac also greatly enhanced their antitumor effects 12, 13, 14, 15, 16.…”