Scientists have discovered a new checkpoint inhibitor that is downstream of p53, a transcription factor that is mutated in a large fraction of all cancers but has been notoriously hard to target therapeutically.

Moreover, the protein – DD1 alpha – appears to connect two key processes, namely, the efficient removal of dead cells and the prevention of an immune response to those cells.

The paper "connects these two key processes – 'eat me' and immune tolerance," co-author Anna Mandinova told BioWorld Today.

As far as cell death is concerned, the immune system's job is akin to finding a needle in a haystack – cells whose death warrants an immune response.

Cell death, senior author Sam Lee of Massachusetts General Hospital told BioWorld Today, is constantly happening – there are billions of cells dying daily.

Most of those deaths occur via apoptosis, or programmed cell death, and do not warrant any attention from the immune system.

In their findings, the team found that DD1 alpha was expressed on the surface of three separate cell types: cells that were dying of natural causes, macrophages that could dispose of them and T cells that could potentially mount an autoimmune response to antigens released from dying cells.

Interactions between DD1 alpha on separate cell types served both to attract the macrophages, and to inhibit the T cells.

If dead cells accumulate in tissues, sooner or later, they are likely to lead to autoimmune responses.

One of the keys to avoiding such an autoimmune response is to get rid of them rapidly. When dead cells are not rapidly cleared, Lee said, "it causes a lot of problems."

Lee's laboratory is focused on p53, which is mutated in more than half of human cancers. P53 is a tumor suppressor that affects cell growth acts via multiple different mechanisms.

The team identified DD1 alpha during a search for downstream targets of p53. But in terms of its function, DD1 alpha appeared to be "very different from any other known downstream target p53 gene," Lee said.

When the team searched for homologies with other proteins to get clues about the protein's possible function, they found that DD1 alpha had "high homology to immune checkpoint inhibitors."

Immune checkpoint inhibitors, such as CTLA-4 and PD-1, prevent the immune system from attacking its own tissues, or continuing an attack beyond the point where it is useful.

Tumor cells subvert such checkpoints via multiple mechanisms, which allows them to escape the immune system and grow. In recent years, checkpoint inhibitors such as Yervoy (ipilimumab, Bristol-Myers Squibb Co.), Keytruda (pembrolizumab, Merck & Co. Inc.) and Opdivo (nivolumab, Bristol-Myers Squibb Co.) have been able to rouse the immune system, and lead to long-term control of cancers, in some fraction of patients that are treated with them.

DD1 alpha exerts its effects when the same surface molecule on different cells interact with each other, an example of a so-called homophilic interaction.

In their experiments, which were published in the July 30, 2015, online issue of Science, the authors showed that several different interactions contributed to the effects of DD1-alpha on immunity.

Dying cells interacted with macrophages to further their own clearance. The macrophages, on the other hand, interacted with T cells via DD1 alpha to promote tolerance to antigens form the dead cells they had engulfed.

Finally, interactions between several dying cells via DD1 alpha appeared to make them more visible to macrophages, ensuring their speedy dispatch.

In a commentary that accompanied the paper, researchers from the French Gustave Roussy cancer campus cautioned that although DD1 alpha knockout mice are prone to autoimmunity, "it may be an oversimplification to directly connect deficient p53 to deficient DD1alpha expression and autoimmunity."

P53 appears to affect several checkpoints, and its broad roles make it possible that the link is indirect. Nevertheless, the commentary authors said the links uncovered in the paper warranted further investigation.

And Lee said that based on public databases, DD1-alpha appears to be expressed at high levels on tumor cells, which suggests that it may be another immune system restrain that tumor cells have co-opted for their own purposes. Targeting DD1 alpha could thus be an additional way to keep tumor cells from co-opting checkpoint inhibition.