Oncolytic virus: A catalyst for the treatment of gastric cancer

Abstract

Gastric cancer (GC) is a leading contributor to global cancer incidence and mortality. According to the GLOBOCAN 2020 estimates of incidence and mortality for 36 cancers in 185 countries produced by the International Agency for Research on Cancer (IARC), GC ranks fifth and fourth, respectively, and seriously threatens the survival and health of people all over the world. Therefore, how to effectively treat GC has become an urgent problem for medical personnel and scientific workers at this stage. Due to the unobvious early symptoms and the influence of some adverse factors such as tumor heterogeneity and low immunogenicity, patients with advanced gastric cancer (AGC) cannot benefit significantly from treatments such as radical surgical resection, radiotherapy, chemotherapy, and targeted therapy. As an emerging cancer immunotherapy, oncolytic virotherapies (OVTs) can not only selectively lyse cancer cells, but also induce a systemic antitumor immune response. This unique ability to turn unresponsive 'cold' tumors into responsive 'hot' tumors gives them great potential in GC therapy. This review integrates most experimental studies and clinical trials of various oncolytic viruses (OVs) in the diagnosis and treatment of GC. It also exhaustively introduces the concrete mechanism of invading GC cells and the viral genome composition of adenovirus and herpes simplex virus type 1 (HSV-1). At the end of the article, some prospects are put forward to determine the developmental directions of OVTs for GC in the future.

Keywords: adenovirus; combination therapy; gastric cancer; herpes simplex virus type 1; oncolytic virus; tumor microenvironment.

Figure 1

OVs can selectively infect and lyse cancer cells locally. (A) Following viral infection, most normal cells activate antiviral pathways against viral infections. The antiviral machinery can be triggered by viral PAMPs that activate PRRs (such as cGAS for DNA viruses and RIG-I for RNA viruses). Once PAMPs are detected, a signaling cascade through the adaptor molecule STING or MAVS phosphorylating IRF3 and NF-κB to dimerize and translocate to the nucleus to regulate the programmed transcription of type I IFN and proinflammatory cytokines. Among them, proinflammatory cytokines recruit immune cells to infiltrate the TME, and local IFN production can promote antiviral activity through IFNR. Upon type I IFN binding to receptors, the activated JAK-STAT signaling pathway leads to the rapid transcription of abundant ISGs to inhibit various stages of the viral lifecycle from invasion to release and can even target infected cells for apoptosis or necrosis. (B) In malignant cells, this process is disrupted. Cancer cells may increase the number of viral receptors or downregulate key signaling components within the innate antiviral signaling pathway, including PPRs, STING, MAVS, type I IFN and ISGs, thereby limiting their proapoptotic and cell cycle regulatory effects. Therefore, OVs can easily reach the critical value of viral load for oncolysis. OV, oncolytic virus; PAMPs, pathogen-associated molecular patterns; DAMPs, damage-associated molecular patterns; PRRs, pattern-recognition receptors; dsDNA, double-stranded linear DNA; dsRNA, double-stranded linear RNA; cGAS, cyclic GMP–AMP synthase; ATP, adenosine triphosphate; GTP, guanosine triphosphate; cGAMP, cyclic GMP–AMP; ER, endoplasmic reticulum; TBK1, TANK-­binding kinase 1; IKK, IκB kinase; IRF3, interferon regulatory factor 3; NF-κB, nuclear factor-κB; RIG-I, retinoic acid-inducible gene I; TNF-α, tumor necrosis factor-α; IL-6, interleukin-6; ISGs, interferon-stimulated genes; IFN, interferon; IFNR, interferon receptor; JAK, Janus kinase; STAT, signal transducer and activator of transcription; TME, tumor microenvironment.

Figure 2

OVs can stimulate a systemic adaptive antitumor immune response. Cancer cells are lysed by mature OVs to release viral progeny, TAAs, PAMPs and DAMPs into the TME. Among them, progeny virions will ceaselessly infect the surrounding cancer cells to establish a cascade amplification reaction to eliminate malignancy. Infiltrative APCs can swallow and process TAAs, PAMPs, and DAMPs to present neoantigens by MHC molecules for the activation of immune cells. The sensitized CTLs attack the identified cancer cells by releasing perforin and granzyme B, and the activated Th cells can stimulate B cells to promote their activation and secrete neutralizing antibodies, which can mark malignant cells for ADCC by NK cells or ADCP by macrophages. Finally, immune effector cells, immune effector molecules and progeny virions will travel through the body with the blood to initiate a systemic adaptive antitumor immune response. APC, antigen-presenting cell; NK, natural killer cell; MHC, major histocompatibility complex molecule; CTL, cytotoxic T lymphocyte; Th, T helper cell; ADCC, antibody-dependent cellular cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; PAMPs, pathogen-associated molecular patterns; DAMPs, damage-associated molecular patterns; TCR, T-cell receptor; BCR, B-cell receptor; TAA, tumor-associated antigen.

Figure 3

The internal structure and invasive process of adenovirus. Infection with adenovirus is mainly initiated by high affinity binding of fiber protein to CAR, with the participation of αvβ3/αvβ5 integrins as secondary receptors. Endocytic virions are released from lysosomes and transferred to the nucleus through nuclear pore complexes for transcription and translation. The adenoviral genome contains two ITRs at both ends, the packaging signal Ψ, and the major functional genes, such as early transcription units E1~E4 and late transcription units L1~L5. CAR, coxsackievirus adenovirus receptor; RGD, arginine-glycine-aspartate; LITR, left inverted terminal repetitions; RITR, right inverted terminal repetitions; Ψ, packaging signal; E1~E4, early transcription units; L1~L5, late transcription units; MLP, major late promoter.

Figure 4

The internal structure and invasive process of HSV-1. HSV-1 requires viral binding to specific receptors to trigger membrane fusion to enter host cells. First, gB and/or gC binding to HS facilitates viral adsorption to the cells. Then, one of several entry receptors, including HVEM, Nectin-1 or -2, and 3-OS HS, can bind to gD to stabilize the attachment and promote the formation of the gH-gL complex. Subsequently, the gH–gL complex activates gB to interact with NMHC-IIA/B, PILRα or MAG. Finally, the gD, gB, and gH-gL complexes and their cognate receptors form the core fusion complex to initiate the fusion reaction of the viral envelope with the cytoplasmic membrane. The genomic DNA of HSV-1 is divided into UL, US, TRL, IRL, TRS, and IRS, which can be segmented into immediate-early (IE), early (E) and late (L) for their respective functions. HSV-1, herpes simplex virus type 1; gB, gC, gD, gH, and gL, viral entry glycoproteins; HS, heparan sulfate; HVEM, herpesvirus-entry mediator; 3-OS HS, 3-O-sulfated heparan sulfate; NMHC-IIA/B, non-muscle myosin heavy chain II A/B; PILRα, paired immunoglobulin-like receptor α; MAG, myelin-associated glycoprotein; UL/US, unique sequence of the long/short region; TRL/IRL, terminal/internal inverted repeat sequence of the long region; TRS/IRS, terminal/internal inverted repeat sequence of the short region; ICP, infected cell protein; TK, thymidine kinase.

Figure 5

The expression levels of some genes in various tissues based on the GEPIA online database (http://gepia.cancer-pku.cn/index.html). AFP, alpha-fetoprotein; LIHC; liver hepatocellular carcinoma; PSA, prostate-specific antigen; PRAD, prostate adenocarcinoma; STAD, stomach adenocarcinoma; CEA, carcinoembryonic antigen; COAD, colon adenocarcinoma; READ, rectum adenocarcinoma; LUAD, lung adenocarcinoma; HER2, human epidermal growth factor receptor 2; MUC1, mucin 1; EpCAM, epithelial cell adhesion molecule; CLDN 18.2, claudin 18.2; MSLN, mesothelin; FOLR1, folate receptor 1; PGA, pepsinogen; PGC, gastricsin; CBLIF, cobalamin binding intrinsic factor.