Overexpression of transposable elements is associated with immune evasion and poor outcome in colorectal cancer

Abstract

AIM: High immune cell infiltration of the tumour microenvironment is generally associated with a good prognosis in solid cancers. However, a subset of patients with colorectal cancer (CRC) tumours with high immune cell infiltration have a poor outcome. These tumours have a high level of T cell infiltration and are also characterised by increased expression of programmed death-ligand 1 (PD-L1). As these tumours comprise both microsatellite instability and microsatellite stable subtypes, the mechanism underlying this phenotype is unknown. METHODS: Using RNA-seq data from The Cancer Genome Atlas, we quantified transposable element (TE) expression and developed a TE expression score that is predictive of prognosis and immune infiltration independent of microsatellite instability status and tumour staging in CRC. RESULTS: Tumours with the highest TE expression score showed increased immune cell infiltration with upregulation of interferon (IFN) signalling pathways and downstream activation of IFN-simulated genes. As expected, cell lines treated with DNA methyltransferase inhibitor mimicked patient tumours with increased TE expression and IFN signalling. However, surprisingly, unlike high TE expressing CRC, there is little evidence for the activation of JAK-STAT signalling and PD-L1 expression in DNA methyltransferase inhibitor-treated cells. Single-cell RNA-seq analysis of CRC samples showed that PD-L1 expression is mainly confined to tumour-associated macrophages and T cells, suggesting that TE mediated IFN signalling is triggering expression of PD-L1 in immune cells rather than in tumour cells. CONCLUSIONS: Our study uncovers a novel mechanism of TE driven immune evasion and highlights TE expression as an important factor for patient prognosis in CRC.