Factors that regulate the immune system play a key role in maintaining the balance of the immune system. If the immune system is too active, the body might be in a risk of developing autoimmune diseases such as rheumatoid arthritis. Otherwise, if the immune system is too passive, cancer cells and infections can grow uncontrolledly. A key regulator is the inhibitory co-receptor PD-1. Antibodies to this co-receptor, called checkpoint inhibitors, have successfully activated the immune system to attack cancer cells, although their responses are not always successful and they themselves are not long-lived.

In a study published in Immunity, researchers led by Dr. Shoba Amarnath investigated factors that inhibit PD-1 activation in immune cells. One such factor is the enzyme AEP. In the absence of AEP, mice are resistant to developing autoimmune diseases but sensitive to tumor cells.

Dr. Amarnath explained: "We found in laboratory studies that AEP enhances the role of these checkpoint inhibitor drugs in advanced melanoma.” When higher levels are found in T cells of the immune system, AEP works in combination with checkpoint inhibitors in many diseases. By opening the immune system and preventing graft-versus-host disease, it succeeds in attacking tumor cells in skin cancer.

It's worth noting that although scientists have previously known the existence of AEP, until now, its importance in helping the immune system cope with any condition is still not fully understood. Since AEP is required for PD-1 inhibitors to enhance the immune response, measuring AEP levels may be helpful in identifying patients most likely to respond to immune checkpoint inhibitor treatment of PD1 and PDL1.

Learn why checkpoint inhibitors work

A team led by Dr. Amarnath has determined how tumor-attacking immune cells are inactivated in the tumor microenvironment. CD4 + T helper cells are immune cells that recognize and kill infected cells and cancer cells. These cells are also responsible for autoimmune diseases and transplant rejection. Because these cells kill healthy tissue, their activity is tightly controlled by another immune cell called regulatory T cells.

It has been suggested that the protective activity of regulatory T cells interferes with immunotherapy treatment. The local environment of some tumors enhances the formation of regulatory T cells, which in turn limits the activation of anti-cancer T cells.

When Dr. Amarnath's team studied how PD-1 blocks these anti-cancer cells, they found that PD-1 specifically down-regulates a new enzyme called asparaginyl endopeptidase (AEP), which in the melanoma tumor environment alters the key to the balance between anti-cancer cells and regulatory T cells.

These findings indicate that in the absence of AEP, checkpoint inhibitors may have no beneficial response, and measuring AEP protein levels in patients prior to treatment with checkpoint inhibitors may provide a better response rate for cancer immunotherapy regimens. Similarly, in mice, when researchers turn on PD-1 signaling and block AEP in T cells, they produce powerful T-regulatory cells that prevent inflammatory diseases such as colitis and graft versus host disease. This finding may be able to generate new immunotherapeutic treatments for patients who currently do not respond to standard treatment regimens for colitis and graft versus host disease.

Currently, immune checkpoint inhibitors have been used in combination with each other, and combination with chemotherapy has also been shown to increase patient response rates. In the case of combined targeted drugs, many small molecule inhibitors have been researched and applied, such as pkd inhibitor, sigma receptor inhibitor, xanthine oxidase inhibitor, stearoyl-coa desaturase inhibitor, slc9a3 inhibitor, amyloid precursor protein secretase inhibitor, lpxc inhibitor, prostanoid receptor inhibitor, apoptosis signal-regulating kinase 1 inhibitor, eribulin, dubs inhibitor, potassium voltage-gated channel inhibitor, Sphingosine-1-phosphate receptor 3 Inhibitor, pdk-1 inhibitor, thrombopoietin receptor inhibitor, rhinovirus inhibitor, rad51 inhibitor and more.

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BOC Sciences