Overexpression of transposable elements underlies immune overdrive and poor clinical outcome in cancer patients

The immune system plays a key role in protection against cancer. Increased immune infiltration in tumor tissue is usually associated with improved clinical outcome, but in colorectal cancer, excessive immune infiltration has also been shown to lead to worst prognosis. The factors underlying this immune overdrive phenotype remains unknown. In this study, using colorectal cancer as a model, we develop a transposable element (TE) expression score that stratifies patients into four clusters with distinctive prognosis. Those with the highest TE expression are associated with immune overdrive and have the poorest outcomes. Importantly, this association is independent of microsatellite instability status and tumor mutation burden. To demonstrate that TE reactivation is responsible for the immune overdrive phenotype, we show that cell lines treated with DNA methyltransferase inhibitors also have a high TE expression score and activation of cellular innate immune response pathways. Finally, a pan-cancer survey of TE expression identify a subset of kidney renal clear cell carcinoma with a similar adverse immune overdrive phenotype with poor prognosis. Together, our findings reveal that TE expression underlies the immune overdrive phenotype in cancer and is predicative of immune infiltration and patient prognosis in cancer patients.