A new strategy for treating colorectal cancer: Regulating the influence of intestinal flora and oncolytic virus on interferon

Abstract

Colorectal cancer (CRC) has the third highest incidence and the second highest mortality in the world, which seriously affects human health, while current treatments methods for CRC, including systemic therapy, preoperative radiotherapy, and surgical local excision, still have poor survival rates for patients with metastatic disease, making it critical to develop new strategies for treating CRC. In this article, we found that the gut microbiota can modulate the signaling pathways of cancer cells through direct contact with tumor cells, generate inflammatory responses and oxidative stress through interactions between the innate and adaptive immune systems, and produce diverse metabolic combinations to trigger specific immune responses and promote the initiation of systemic type I interferon (IFN-I) and anti-viral immunity. In addition, oncolytic virus-mediated immunotherapy for regulating oncolytic virus can directly lyse tumor cells, induce the immune activity of the body, interact with interferon, inhibit the anti-viral effect of IFN-I, and enhance the anti-tumor effect of IFN-II. Interferon plays an important role in the anti-tumor process. We put forward that exploring the effects of intestinal flora and oncolytic virus on interferon to treat CRC is a promising therapeutic option.

Keywords: basic mechanism; colorectal cancer; interaction; interferon; intestinal flora; oncolytic virus.

Graphical abstract

Figure 1

The main action pathway of IFN in inhibiting tumor cells IFN-I can activate DCs, increase the cytolytic activity of macrophages and NK cells, induce the production of IL-15, activate T cells, and increase the survival of T cells. The IFN-γ signal cascade pathway is the main anti-tumor pathway of IFN-II. IFN-γ binds to IFN-γ receptors (IFNGRs) on tumor cells and stimulates Janus kinase (JAK) signal transduction and transcription (STAT) activator signaling pathway, which stimulates phosphorylation and nuclear translocation of STAT1, thus activating the IFN-stimulated gene transcription program and regulating the immune response. IFN-γ enhances the production of MHC-I and MHC-II in cancer cells and IL-12 in APC, promotes Th1 polarization, and promotes tumor transport of immune cells through the secretion of Th1 chemokines, thus achieving the anti-tumor purpose.

Figure 2

The mechanism of inflammatory reaction and oxidative stress reaction of intestinal flora In inflammatory reactions, symbiotic microorganisms can regulate the adaptive immune system in various ways. Symbiotic microorganisms produce adaptive immune responses by stimulating the differentiation of Th17 cells and Treg cells, among which Treg cells exert immunosuppressive function on various immune cells through IL-10 and TGF-β. Th17 cells acquire pathogenic inflammatory phenotype with IL-23 and SAP, and they promote the release of IL-17. In the oxidative stress reaction, inflammatory cells, including neutrophils, macrophages, and lymphocytes, produce a large number of ROS and RNS under the stimulation of inflammation, which leads to DNA damage. Anaerobic bacteria activated TLR2/TLR4 on intestinal epithelial cells (IECs) and increased the level of ROS in cells. E. coli and ETBF also stimulate ROS production and cause DNA damage. Inflammation and oxidative stress promote each other, which further leads to the occurrence of CRC.

Figure 3

OV is a new therapeutic drug that promotes anti-tumor response through the dual mechanism of selective tumor cell killing and inducing systemic anti-tumor immunity OV selectively infects and kills tumor cells, but virus replication does not occur in normal cells of the human body, so normal cells continue to survive. However, when the OV infects tumor cells, viral replication leads to the accumulation of p53 and activation of caspase-8 proenzyme, leading to tumor cell apoptosis and lysis. Besides directly cracking cancer cells, the OV also attacks tumor blood vessels and causes vascular atrophy, among which JX-594 can cause acute tumor blood vessel destruction, and, at the same time, the OV can downregulate the secretion of VEGF by tumor cells and surrounding uninfected cells and inhibit the formation of tumor vascular system. In addition, IL-2 expressed by VSV can reduce regulatory T cells in the neovascular system and tumor tissues. Compared with directly cracking cancer cells and attacking tumor blood vessels, inducing immune activity is more important. In the process of virus oncolysis, OVs replicated in tumor cells are released, as well as CRT, HSPs, HMGB1, TAA, cell death signals, endogenous risk signals, and tumor-derived cytokines. Among them, immunogenic death leads to the exposure or release of PAMPs and TAAs as danger signals. PAMPs activate a series of signals, stimulate inflammatory corpuscles, and release pro-inflammatory cytokines and DAMPs, thus breaking the immunosuppressive state of tumors. In addition, virus oncolysis can also recruit immune cells that release cytokines. OV infection can activate the TLR signaling pathway in the tumor site, resulting in the release of cytokines GM-CSF, IL-2, IL-6, IL-12, IL-18, and IFN-γ, and chemokines, which can directly have toxic effects on tumor cells, stimulate chemotactic cells to infiltrate into the tumor site, and induce anti-tumor immunity. At the same time, cell death signals, TAA, endogenous danger signals, tumor-derived cytokines, and immunoregulatory factors released in the process of oncolysis can activate immune cells such as DCs, NK cells, macrophages, and neutrophils, and activate the innate immune response of the body. At the same time, after the OV infects tumor cells, it is easy to start adaptive immune effect, promote MHC-I expression, activate CD8+T cells, and promote the formation of MHC-II.