Molecular Mechanisms of Anti-Neoplastic and Immune Stimulatory Properties of Oncolytic Newcastle Disease Virus

Abstract

Oncolytic viruses represent interesting anti-cancer agents with high tumor selectivity and immune stimulatory potential. The present review provides an update of the molecular mechanisms of the anti-neoplastic and immune stimulatory properties of the avian paramyxovirus, Newcastle Disease Virus (NDV). The anti-neoplastic activities of NDV include (i) the endocytic targeting of the GTPase Rac1 in Ras-transformed human tumorigenic cells; (ii) the switch from cellular protein to viral protein synthesis and the induction of autophagy mediated by viral nucleoprotein NP; (iii) the virus replication mediated by viral RNA polymerase (large protein (L), associated with phosphoprotein (P)); (iv) the facilitation of NDV spread in tumors via the membrane budding of the virus progeny with the help of matrix protein (M) and fusion protein (F); and (v) the oncolysis via apoptosis, necroptosis, pyroptosis, or ferroptosis associated with immunogenic cell death. A special property of this oncolytic virus consists of its potential for breaking therapy resistance in human cancer cells. Eight examples of this important property are presented and explained. In healthy human cells, NDV infection activates the RIG-MAVs immune signaling pathway and establishes an anti-viral state based on a strong and uninhibited interferon α,ß response. The review also describes the molecular determinants and mechanisms of the NDV-mediated immune stimulatory effects, in which the viral hemagglutinin-neuraminidase (HN) protein plays a prominent role. The six viral proteins provide oncolytic NDV with a special profile in the treatment of cancer.

Keywords: NK cell; T cell; autophagy; cancer immunotherapy; cancer therapy resistance; cancer vaccine; dendritic cell; exosome; immunogenic cell death; interferon-Ι.

Figure 1

Schematic illustration of mechanisms of anti-tumor activity of NDV. This is exemplified with a migratory and invasive glioblastoma (GBM) cell. The direction of cell movement is accompanied by an increase in Rac1 expression from the trailing edge (left) to the leading edge at the lamellipodia (right) [151]. 1. Macropinocytosis/endocytosis of NDV-targeting Rac1, which plays a cardinal role in oncogenic alterations and in the development of drug resistance [152]. The direction of cell movement is accompanied by an increase in Rac1 expression from the trailing edge (left) to the leading edge at the lamellipodia (right) [151]. 2. Targeting the cap-dependent translational machinery; viral mRNA to protein translation in the cytosol and later in the double-membraned autophagosome (see GBM). This is achieved through the MNK1/2-eIF4E axis [35,36]. 3. Tumor-selective virus replication in autophagosomes. The clam shaped symbol stands for the helical nucleocapsid structure composed of L, P, and NP proteins [5,6]. 4. Virus progeny encapsulation, budding, and virus release mediated via M, HN, and F. 5. Antiviral response of healthy normal cells, including immune cells (APC, T, NK) initiated through recognition of HN by NKp46 and other PAMPs by TLRs and RLRs leading to IFN-I secretion and to DC1 and Th1 polarized adaptive immunity responses. 6. NDV-induced tumor cell death responses (oncolysis). These involve extrinsic (immune-mediated) and intrinsic cell death signaling pathways [98]. ICD-derived components feed into APCs which present TAAs to T cells. Several rounds of such cycles (1–6) drive oncolytic effects and lead to immunological memory and systemic antitumor immunity.