Characterising Long Non-Coding RNAs (lncRNAs) Associated with a Protective Type 1 Interferon (IFN) Gene Signature in Tumour and Immune cells

Abstract

Type 1 interferons have emerged as critical regulators of cancer immunity. By inducing the transcription of interferon-stimulated genes (ISGs), these cytokines can directly inhibit tumour proliferation and mediate apoptosis, as well as enhancing immunosurveillance through activation of innate and adaptive effectors. However, dose-dependent toxicities and tumour-promoting immunosuppression have limited their use in the clinic. Current efforts are aimed at modulating the endogenous type 1 IFN response with precision immunotherapies. One promising category of molecular targets is long non-coding (lncRNAs), which are aberrantly expressed in many tumour types. We analysed The Cancer Genome Atlas (TCGA) sequencing datasets and selected 38 abundant lncRNA transcripts that were expressed in most patients and had a significant association with the type 1 IFN response and survival. We subsequently validated them by siRNA knockdown in an ISG54/ISRE inducible luciferase reporter system and found 12 genes that differentially affected type 1 IFN signalling. Using NanoString, we profiled 59 IFN signature genes in tumour and immune cells overexpressing lncRNA transcripts to identify positive and negative regulators of the type 1 IFN response. This study presents a high-throughput approach for discovering potentially immunostimulatory lncRNA molecules and elucidating their regulatory roles in cancer.