Epigenetic Silencing of IRF7 and/or IRF5 in Lung Cancer Cells Leads to Increased Sensitivity to Oncolytic Viruses

Qunfang Li,Michael A Tainsky,Masaru Katoh

doi:10.1371/journal.pone.0028683

Qunfang Li, Michael A Tainsky + Show 1 more

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https://doi.org/10.1371/journal.pone.0028683

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Abstract

Defective IFN signaling results in loss of innate immunity and sensitizes cells to enhanced cytolytic killing after Vesticular Stomatitis Virus (VSV) infection. Examination of the innate immunity status of normal human bronchial epithelial cells Beas2B and 7 lung cancer cells revealed that the abrogation of IFN signaling in cancer cells is associated with greater sensitivity to VSV infection. The disruption of the IFN pathway in lung cancer cell lines and primary tumor tissues is caused by epigenetic silencing of critical interferon responsive transcription factors IRF7 and/or IRF5. Although 5-aza-2′-deoxycytidine treatment fails to reactivate IRF7 and IRF5 expression or protect cells from VSV infection, manipulating IFN signaling by altering IRF expression changes the viral susceptibility of these cells. Lung cancer cells can be partially protected from viral killing using IRF5+IRF7 overexpression, whereas IFN pathway disruption by transfection of siRNAs to IRF5+IRF7 increases cells' vulnerability to viral infection. Therefore, IRF5 and IRF7 are key transcription factors in IFN pathway that determine viral sensitivity of lung cancer cells; the epigenetically impaired IFN pathway in lung cancer tissues provides potential biomarkers for successful selective killing of cancer cells by oncolytic viral therapy.

Highlights

As the leading cause of cancer-related mortality in both men and women, lung cancer is responsible for well over 1 million deaths worldwide annually
IFN signaling deficiency is associated with Vesticular Stomatitis Virus (VSV) sensitivity The IFN pathway controls the cellular response to viral infection and dsRNA
Because functional inactivation of IFN pathway has been a common trait of many cancers, we used 7 long-term lung cancer cell lines (4 adenocarcinomas: CRL5800, CRL5807, CRL5810 and CRL5872, 2 squamous carcinomas: HTB172 and CRL5928 and 1 small cell carcinoma: CRL5869) to study the changes in their innate immune system

Summary

Introduction

As the leading cause of cancer-related mortality in both men and women, lung cancer is responsible for well over 1 million deaths worldwide annually. Diagnosis and treatment have been improved, the five-year survival rate is only 14% largely due to the failure of tumor debulking surgery and systemic chemotherapy. The improvement of lung cancer treatment is a major public health goal. Used alone or in combination with chemotherapy, oncolytic viruses selectively destroy tumor cells by targeting cancer defects in major pathways, such as p53 tumor suppressor, ras signal transduction and IFN signaling pathways [1,2]. The effectiveness and safety of different oncolytic viruses in treatment of various cancers is being evaluated in preclinical animal models and phase I–III clinical trials [3]. A negative strand RNA virus VSV, which can trigger innate immunity mechanisms, has been shown to be efficacious against malignant glioma, melanoma, leukemias, hepatocellular, breast, bladder and prostate cancers that have defective antiviral responses. A negative strand RNA virus VSV, which can trigger innate immunity mechanisms, has been shown to be efficacious against malignant glioma, melanoma, leukemias, hepatocellular, breast, bladder and prostate cancers that have defective antiviral responses. [4,5,6,7]

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