Multi-modal Anti-cancer Activities Provided by a Non-replicating Sendai Virus Envelope

Abstract

Recently, substantial attention has been focused on cancer treatments using oncolytic viruses, which may result in a paradigm shift in conventional cancer therapy through the use of these viruses either alone or in combination with other therapeutics. Thus far, the cancer-killing mechanism of oncolytic viruses has been dependent on selective viral replication in cancer cells. However, UV-irradiated Sendai virus particles (hemagglutinating virus of Japan envelope; HVJ-E) with membrane fusion activity selectively induce apoptosis in human cancer cells but not non-cancerous cells, although neither viral genome replication nor viral protein synthesis occurs in infected cells. The mechanism of HVJ-E-induced cancer cell killing involves the introduction of viral genome RNA fragments into the cytoplasm via membrane fusion and the subsequent activation of a retinoic acid-inducible gene-I (RIG-I)-like receptor signal, which results in the upregulation of apoptotic genes such as tumor necrosis factor-related apoptosis inducing ligand (TRAIL) and Noxa through the phosphorylation of interferon-regulatory factor (IRF)-3 and -7. In neuroblastoma cells lacking caspase 8, HVJ-E induces programmed necrosis (necroptosis) through the activation of cytoplasmic calcium, which in turn activates calcium-calmodulin-depedent protein kinase to phosphorylate receptorinteracting protein (RIP)-1 and -3. In addition to directly killing cancer, HVJ-E elicits anti-tumor immunity by recruiting immune cells to the tumor microenvironment, facilitating the maturation of dendritic cells, enhancing natural killer (NK) cell activity and ultimately activating killer T cells targeting cancers. Anti-tumor immunity is also achieved via the RIG-I-like receptor signal triggered by cytoplasmic viral RNA fragments, independent of toll-like receptor signaling. Moreover, the fusion protein of HVJ-E acts directly on dendritic cells and macrophages to produce interleukin (IL)-6, which attenuates the function of regulatory T cells. Thus, HVJ-E provides a multi-modal strategy for cancer therapy. Keywords: Anti-tumor immunity, apoptosis, oncolytic virus, RIG-I-like receptor, sendai virus, viral RNA, virosome.