Overexpression of transposable elements is associated with immune overdrive and poor clinical outcome in colorectal cancer patients
Authors: Zhu Xiaoqiang , Fang Hu , Gladysz Kornelia , Barbour Jayne A. , Wong Jason W. H. 
Published: July 2020

Objective

The immune system plays a key role in protecting against cancer. Increased immune infiltration in tumor tissue is usually associated with improved clinical outcome, but in colorectal cancer (CRC), excessive immune infiltration has also been shown to lead to worst prognosis. The factors underlying this immune overdrive phenotype remains unknown.

Design

Using RNA sequencing data from The Cancer Genome Atlas, the expression of over 1,000 transposable element (TE) subfamilies were quantified using the “REdiscoverTE” pipeline. Candidate prognostic and immunogenic TEs were screened by survival and correlation analysis, respectively. Based on these candidates, a TE expression score was developed and CRC patients were clustered using the “kaps” algorithm.

Results

In CRC, we found that the TE expression score stratified patients into four clusters each with distinctive prognosis. Those with the highest TE expression were associated with immune overdrive and had the poorest outcomes. Importantly, this association was independent of microsatellite instability status and tumor mutation burden. To link TE overexpression to the immune overdrive phenotype, we showed that cell lines treated with DNA methyltransferase inhibitors also had a high TE expression score and activation of cellular innate immune response pathways. Finally, a pan-cancer survey of TE expression identified a subset of kidney renal clear cell carcinoma with a similar adverse immune overdrive phenotype with poor prognosis.

Conclusion

Our findings reveal that TE expression is associated with immune overdrive in cancer and is an independent predictor of immune infiltration and prognosis in CRC patients.

1.

What is already known about this subject?

Cancers with high immune infiltration generally have better prognosis, but it is unknown why a subset of colorectal cancers (CRC) with high immune infiltration have the poorest outcomes.

Transposable element (TE) expression has been shown to be strongly associated with immune infiltration in cancers but its role in patient prognosis is unclear.

TEs can be reactivated by DNA hypomethylation in cancers, resulting in immune response via viral mimicry.

2.

What are the new findings?

A TE expression score has been developed that is predicative of prognosis in CRC patients where those who have the highest TE score show an immune overdrive phenotype and have the worst prognosis.

The TE expression score predicts prognostic and immune infiltration independent of microsatellite instability and tumor mutation burden (TMB).

Immune response pathways and infiltrate profiles of high TE expression CRC recapitulates those of DNA methyltransferase inhibitor treated cells where TEs are reactivated, suggesting that TE overexpression may drive immune infiltration in CRC.

A pan-cancer analysis found that kidney renal clear cell carcinoma shares are a similar TE expression associated immune overdrive phenotype with adverse prognosis.

3.

How might it impact on clinical practice in the foreseeable future?

Our work highlights the importance of TE expression in evaluating CRC patient prognosis.

The association of TE expression with the immune overdrive phenotype independent of MSI and TMB status suggests that by considering TE expression, there may be new opportunities to identify MSS CRC patients for immunotherapy and develop new strategies to harness TE driven immune response.