Recent research from Washington University School of Medicine in St. Louis suggests that transposable elements in various cancers potentially could also be used to harness novel immunotherapies against tumors that do not typically reply to immune-based treatments. Shown is a 3D rendering of cancer cells.

Jumping genes are short sections of DNA which were incorporated randomly into the human genome over the long course of evolution. Also called transposable elements, these pieces of DNA have been implicated in the event of cancer.

But recent research from Washington University School of Medicine in St. Louis suggests that transposable elements in various cancers potentially could also be used to direct novel immunotherapies to tumors that do not typically reply to immune-based treatments.

The study is offered online within the journal Nature Genetics.

Immunotherapy is commonly handiest in tumors with quite a few mutations, corresponding to skin and lung cancers. Mutations in DNA cause cancer cells to provide unusual proteins that distinguish tumor cells from normal cells and function targets — called tumor antigens — for immunotherapies, corresponding to antibodies, vaccines and genetically engineered CAR-T cell therapies. But many tumor types don’t contain large numbers of mutations and are due to this fact harder for the immune system to discover as a threat.

Immunotherapy is an especially promising approach for cancer treatment, but current therapies don’t work in lots of tumor types through which the mutation burden is low. “We’re enthusiastic about this research, since it opens up a completely recent method to discover tumor antigens in forms of cancer which have previously been invisible to immunotherapy.”

Ting Wang, PhD, senior writer, the Sanford C. and Karen P. Loewentheil Distinguished Professor of Medicine

Jumping genes — believed to have possibly originated from viruses — are likely to be present in parts of the genome which can be inactive in adult tissues. But past work by Wang and his colleagues showed that these transposable elements sometimes can function as hidden on switches, forcing a gene to be turned on on a regular basis, although it shouldn’t be. As these stealthy on switches drive cancer growth, in addition they can churn out unusual pieces of proteins which can be unique to the tumor and never present in normal cells.

In an evaluation of 33 tumor types from the National Cancer Institute’s The Cancer Genome Atlas Program, the researchers identified 1,068 transposable element-derived transcripts — or sections of RNA made by the cancer cells — with the potential to provide tumor antigens that would function targets for brand new immunotherapies.

Wang and his colleagues determined that these possible tumor antigens were present on the surfaces of cancer cells, making them ideal for targeting with immunotherapies. Importantly, they found that nearly 98% of the greater than 10,000 tumors analyzed had at the least one potential antigen goal arising from a transposable element. Most tumors had from two to 75 possible antigens.

In one other necessary finding, the researchers showed that most of the candidate proteins that would function antigens were present in multiple tumors and, in some cases, across tumor types. Wang and his colleagues speculated that this raises the potential for a universal antigen-based therapy that would treat multiple tumors with a single cocktail targeting several of essentially the most common tumor antigens that arise from jumping genes. For instance, the info suggest that a vaccine with a mix of 20 of essentially the most common protein targets could cover about 75% of patients across 27 cancer types.

“With this evaluation, we are able to envision the design of a cancer vaccine that targets the highest five or top 10 commonest tumor proteins which can be brought on by transposable elements,” said Wang, also a research member of Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “Any such vaccine remains to be just an idea, but we’re excited concerning the potential, because these common targets could cover a big fraction of tumors. Rather more work is essential, but we’re hopeful that this evaluation can function a start line for the event of effective immunotherapies across many more cancer types.”

Source:

Washington University School of Medicine

Journal reference:

Shah, N. M., et al. (2023). Pan-cancer evaluation identifies tumor-specific antigens derived from transposable elements. Nature Genetics. doi.org/10.1038/s41588-023-01349-3.