In recent years, cancer immunotherapy has been transformed by blocking a protein, PD-L1, which acts as a ‘brake' on the immune system. New research from the Crick shows that a soluble form of this protein, generated by a ‘jumping gene’, is a natural blocker of PD-L1 and so can have a similar effect as these drugs, slowing the growth of tumours.
Published in eLife, the study explains how a soluble protein, produced by a gene which has been altered by parasitic DNA, known as a ‘jumping gene’, strengthens the immune system and slows the growth of tumours.
The researchers first looked to identify how the protein is produced, a mechanism which has not yet been fully understood.
By analysing genetic material expressed in various human cancers, they found that a fragment of parasitic DNA which slipped into the human genome many millions of years ago, called a retroelement, is responsible for its production.
This retroelement entered the human gene, CD274. When the DNA in this gene is used as a blueprint to build proteins, the retroelement section is usually missed out. This leads to the production of a ‘normal’ protein, PD-L1, which is embedded in the cell membrane and suppresses a type of immune cell called T cells.
Occasionally however, changes take place in reading the DNA and the retroelement section is included. This alternative reading means the gene instead produces the alternative protein, sPD-L1, which is soluble and secreted by the cell.
When the two forms of this protein are present together, the researchers found that the soluble version outcompetes the normal version to bind to a common receptor used by both the proteins, and this stops the normal version from inhibiting T cells.
As T cells are important in the immune system, by stopping these cells from being inhibited, the soluble protein strengthens the body’s ability to fight disease and infection. The researchers found that mouse tumours grew more slowly when this soluble protein was present.
“As this protein has been conserved in our genome for many generations, and is present in both healthy and diseased tissue, it’s likely it has an important and potentially beneficial biological function,” says Kevin Ng, lead author and PhD student at the Crick’s Retroviral Immunology Laboratory.
While this soluble protein bolsters the immune response, previous research has shown that other soluble forms of PD-L1 weaken the effect of some cancer immunotherapies. This is because these drugs work by targeting the normal PD-L1 protein and stop it from blocking T cells. By binding with the normal protein, the soluble protein prevents these drugs from recognising their target.
“Finding that this soluble protein has the complete opposite effect on the immune system than the membrane-bound protein was a big piece of the puzzle. Nature strives for the opposite and from it generates consonance”, explains George Kassiotis, author and group leader of the Retroviral Immunology Laboratory at the Crick, citing Herakleitos. “It was surprising that evolution has made use of a ‘jumping gene’ to balance the activity of PD-L1. This protein has a really nuanced relationship with human health and more research is needed to fully understand this”.