Enzyme AEP's importance to immunity discovered

July 24, 2018, Newcastle University
Credit: CC0 Public Domain

The importance of the enzyme AEP as a key regulatory of the immune system has been discovered in new research from Newcastle University, UK.

Factors that regulate the immune system play a key role in holding the immune system in balance. Too active and there is a danger of developing autoimmune diseases such as rheumatoid arthritis. Too passive and cells and infections are free to grow. A key regulator is the inhibitory co-receptor PD-1. Antibodies to this co-receptor, known as checkpoint inhibitors, have been successful in activating the immune system to attack cancer cells, although their responses are not always successful or long lived.

In work published in the journal Immunity today, the researchers led by Dr. Shoba Amarnath investigated factors that were inhibited by activating PD-1 in . One such factor was the enzyme AEP. In the absence of AEP, mice were resistant to developing autoimmune but susceptible to tumour cells.

Dr. Amarnath explains: "What we have found in our lab studies is that AEP enhances the effect of these checkpoint inhibitor drugs in advanced melanoma.

"When found in higher levels in the T-cells of the immune system, the supporting AEP worked in combination with the checkpoint inhibitory drug in numerous diseases. It was successful in attacking tumours in skin cancer, by switching on the immune system and in preventing Graft Versus Host Disease, by switching off the immune system.

"Remarkably, while we have known of the existence of AEP, we have not, until now, understood its importance in helping the immune system combat any number of conditions."

As AEP is necessary for PD-1 inhibitors to enhance immune responses, measuring AEP levels may help identify patients who are most likely to respond to treatment with immune checkpoint inhibitors to PD1 and PDL1.

Understanding why check-point inhibitors work

The research team led by Dr. Amarnath has identified how tumour attacking immune cells are made inactive within the tumour microenvironment. CD4+ T helper cells are a type of immune cell that recognize and kill infected cells and . These cells are also responsible for autoimmune disease and transplant rejection. Because these cells can kill healthy tissues their activity is tightly controlled by another type of immune cell known as regulatory T cells.

The protective activity of regulatory T cells has been suggested to interfere with immunotherapy treatments. The local environment of some tumours enhancing the formation of regulatory T cells that in turn limits the activation of cancer fighting T cells.

When Dr. Amarnath's team investigated how PD-1 blocked these cancer fighting cells; they found that PD-1 specifically downregulated a new enzyme called asparaginyl endopeptidase (AEP) which was key to shifting the balance between cancer fighting cells and regulatory T cells within the melanoma tumour environment.

These findings demonstrate that checkpoint inhibitors may not have a beneficial response in the absence of AEP and measuring AEP protein levels in patients prior to treatment with checkpoint inhibitors may provide better response rates to the cancer immunotherapy regimens. Similarly, in mice, when the investigators switched on PD-1 signaling in T cells and blocked AEP, powerful T regulatory were generated that were able to prevent inflammatory diseases such as colitis and Graft versus host disease. This discovery may be able to generate new immunotherapy treatments for patients who currently do not respond to standard treatment regimens for colitis and Graft versus Host Disease.

The Newcastle team now intend to progress the work with the intention of taking it into trials in humans.

Explore further: Breaking through a tumor's defenses

More information: PD-1 Inhibitory Receptor Downregulates Asparaginyl Endopeptidase and Maintains Foxp3 Transcription Factor Stability in Induced Regulatory T cells. Stathopoulou et al. Immunity (2018). doi.org/10.1016/j.immuni.2018.05.006

Related Stories

Breaking through a tumor's defenses

June 7, 2018
In research published today, Babraham Institute researchers have shown that some tumours use not one but two levels of protection against the immune system. Knocking out one level boosted the protective effects of the second ...

Researchers find combination can enhance ipilimumab immunotherapy

June 15, 2018
Using a targeted therapy to block a protein that suppresses T cell activity could improve cancer treatment with immune checkpoint inhibitors, researchers at The University of Texas MD Anderson Cancer Center report today in ...

Research group discovers a new immune system regulator

February 23, 2018
Academy Professor Riitta Lahesmaa's research group at Turku and Åbo Akademi University, Finland, has discovered a new regulator of the immune system, a key factor that controls development of regulatory T cells. The discovery ...

Cancer immunotherapy may work better in patients with specific genes

December 15, 2017
Cancer cells arise when DNA is mutated, and these cells should be recognized as "foreign" by the immune system. However, cancer cells have found ways to evade detection by the immune system.

Cancer immunotherapy may get a boost by disabling specific T cells

September 7, 2017
Cancer immunotherapy drugs only work for a minority of patients, but a generic drug now used to increase blood flow may be able to improve those odds, a study by Columbia University Medical Center (CUMC) researchers suggests.

Recommended for you

Researchers uncover immune cell dysfunction linked to photosensitivity

August 16, 2018
Researchers at Hospital for Special Surgery (HSS) have discovered that a type of immune cell known as Langerhans appears to play an important role in photosensitivity, an immune system reaction to sunlight that can trigger ...

Chemicals found in vegetables prevent colon cancer in mice

August 14, 2018
Chemicals produced by vegetables such as kale, cabbage and broccoli could help to maintain a healthy gut and prevent colon cancer, a new study from the Francis Crick Institute shows.

Researchers artificially generate immune cells integral to creating cancer vaccines

August 14, 2018
For the first time, Mount Sinai researchers have identified a way to make large numbers of immune cells that can help prevent cancer reoccurrence, according to a study published in August in Cell Reports.

Doctors may be able to enlist a mysterious enzyme to stop internal bleeding

August 14, 2018
Blood platelets are like the sand bags of the body. Got a cut? Platelets pile in to clog the hole and stop the bleeding.

Team finds missing immune cells that could fight lethal brain tumors

August 13, 2018
Glioblastoma brain tumors can have an unusual effect on the body's immune system, often causing a dramatic drop in the number of circulating T-cells that help drive the body's defenses.

Cannabis link to relieving intestinal inflammation explained

August 13, 2018
Reports from cannabis users that the drug reduces the symptoms of inflammatory bowel disease (IBD) may finally be explained by new research from the University of Massachusetts Medical School and the University of Bath showing ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.