A recent study has revealed that transposable elements could be a new target for cancer immunotherapy. The work, published in Nature Genetics, shows how dormant transposable elements can come alive in tumours and produce transcripts not found in non-cancerous cells.
Transposable genetic elements are common features in the genome, found across species from bacteria to humans. These small sections of genetic material are mobile and can move around and across genomes. However, in humans, most of these elements are dormant. It has been reported in recent years that epigenetic dysregulation in cancer cells can lead to the reactivation of transposable promoters, causing erroneous gene expression not seen in healthy cells. In addition, these mobile elements can be transcribed alongside protein-coding DNA, leading to the production of unique chimeric transcripts found only in tumours, making them a perfect drug target.
Immunotherapy, a revolutionary treatment approach that turns the immune system against the disease, typically targets proteins exclusively produced in cancer cells in order to avoid killing healthy tissue. Therefore, these unique transposable transcripts, should they be found as antigens on the surface of a cancer cell, could be used as a target for immunotherapies. However, a comprehensive screening of cancer cells has not yet taken place to assess the feasibility of this approach. The current study aimed to combat this, using The Cancer Genome Atlas (TCGA) to find targetable antigens containing transposable DNA.
The study used data from the TCGA, consisting of over 20,000 cancer genomes from 33 different tumour types. The researchers found over 1,000 transposable elements that had the potential to be “exapted” – transcribed following reactivation of cryptic promoters. These transposable elements were transcribed in tandem with regular protein-coding DNA, leading to the formation of the aforementioned unique transcripts that are subsequently translated into protein.
HLA-pulldown mass spectrometry revealed that these unique proteins often present as antigens on the surface of the cell. This was observed in 98% of the analysed samples and makes the proteins prime targets for immunotherapy. In many cases, these transcripts were found in multiple tumour types. These findings could pave the way for the creation of universal therapies to treat multiple cancer types.
Cancer vaccines could be the way forward
Given the unique genetic makeup of most tumours, finding common pathogenic mechanisms is vital. These findings point to new avenue for effective immune-based treatments by identifying novel targets that only exist in cancer cells and not their benign neighbours. The results could lay the groundwork for cancer vaccines, although the team acknowledge that there is still work to do.
Discussing the results, author Ting Wang noted: “With this analysis, we can envision the design of a cancer vaccine that targets the top five or top 10 most common tumor proteins that are caused by transposable elements. This type of vaccine is still just an idea, but we are excited about the potential, because these common targets could cover a large fraction of tumors. Much more work is necessary, but we are hopeful that this analysis can serve as a starting point for the development of effective immunotherapies across many more cancer types.”