Sperm proteins on the wrong side of the fence: implications for the diagnosis and treatment of male infertility……and cancer

Our immune systems develop after birth to recognise and attack foreign proteins but also to learn which proteins are normally present inside our body. When a boy goes through puberty however, sperm start to develop for the first time within his testes, meaning that proteins specifically found in sperm are at risk of being recognised as foreign by the immune system. Scientists have long assumed that these proteins must be restricted inside a “fence” within the sperm-producing tubules of the testis so they can’t be attacked by immune cells or enter the circulation.

Yet surprising new research led by scientists at the Hudson Institute of Medical Research, University of Newcastle and Walter and Eliza Hall Institute shows that many sperm-specific proteins are normally released by the tubules. Once released, they are freely able to interact with the immune system and to enter the circulation. The researchers believe the tubules release these proteins to “tolerise” the immune system; to signal that the proteins are not foreign and help prevent a major immune response if the testis is compromised.

This unexpected finding goes against what is currently known about testis biology, but also has two important implications.

First, the fact that these sperm-specific proteins are released from the tubules and can enter the circulation opens up the possibility of developing a blood test to diagnose fertility and testis function. Almost 10% of infertile men have no sperm in their ejaculate but may have sperm in their testes that could be retrieved surgically and used in IVF. However up to half of these men will have no sperm to be retrieved in their testes, and will thus undergo surgery unnecessarily. This new research shows it is possible to design a blood test to see which men have sperm in their testes. This blood test could be used to better diagnose and rationalise treatment for men with various types of infertility.

Second, the findings also have surprising implications for designing new diagnoses and treatments for cancer. Many cancers express proteins called cancer-testis antigens (CTAs). These are proteins thought to only be expressed in developing sperm and not found elsewhere in the body, but are abnormally produced by certain cancers. Because CTAs are assumed to remain within the testis tubules and to be absent from the circulation in a healthy man, researchers have assumed they would be excellent cancer biomarkers because they should only be detected when they are produced by a cancer. They are also assumed to be excellent targets for cancer immunotherapy because they should generate a strong immune response that could be harnessed to kill cancer cells. However, the new research showed some CTAs are released normally by the tubules in men, suggesting that the immune system may be tolerant to them, and also suggesting they could appear in the circulation of healthy men. This research provides essential information to guide scientists about which CTAs would be the best targets for cancer diagnosis and immunotherapy, and which are less likely to be effective.