T cells are the immune cells responsible for recognizing and destroying specific invaders, such as viruses, bacteria, or cancer. Their activity is highly tunable, with signals from other cells adjusting T cell responses to counteract the invasion. However, sometimes those responses fall short, as in chronic viral infections and cancers that thwart immune responses by inducing T cell dysfunction. Now, a study led by scientists at the Sanford Burnham Prebys Medical Discovery Institute (SBP) identifies a new regulator of immune responses which sheds new light on why T cells fail to clear chronic infections or eliminate tumours. The team state that their findings open the door for a new approach to modulating T cell responses in many clinical settings, including infections, autoimmune diseases, and cancers that are unresponsive to currently available therapies. The opensource study is published in the journal Immunity.
Previous studies show that the recent emergence of drugs that block immune checkpoints has provided a new, improved approach to treating certain cancers such as lung cancer and melanoma. Immune checkpoints act as brakes for T cells, restraining the immune system from self-attack and preventing autoimmune diseases. Inhibitors of checkpoints remove these brakes, and unleash the immune system to tackle these cancers, in some cases extending survival by years. The current study shows that a protein on the surface of T cell, known as P-selectin glycoprotein ligand-1 (PSGL-1), increases the level of immune checkpoints to allow T cell inhibition; when PSGL-1 is missing, the brakes are off, and T cells remain active longer than normal.
The current study utilised a mouse-model engineered to lack PSGL-1. Results show that these mice completely eradicated lymphocytic choriomeningitis virus (LCMV) infections, which normally last months. The lab explain that total clearance of LCMV is rare, so once it was observed that total clearance had indeed happened, it was evident that PSGL-1 was crucial for limiting immune responses.
The group then looked at whether this lack of an immune brake would impact cancer by injecting the same mice with melanoma cells. Results show that tumours grew much slower than they do in normal mice, showing PSGL-1 regulates T cell responses in general.
The lab hypothesize that blocking PSGL-1 may enhance the immune response to cancer and chronic viral infections such as hepatitis. They go on to add that, in contrast, activating PSGL-1 may be a way to inhibit immune responses that could potentially be used to treat autoimmune diseases, such as rheumatoid arthritis, psoriasis, multiple sclerosis and lupus.
The team surmise that their findings show that PSGL-1 acts as a negative regulator of T cell function. They go on to add that PSGL-1 has the broad capacity to dampen T cell signals and promote the exhaustion of T cells in viral and tumour mouse models. For the future, the researchers state that PSGL-1 inhibitors could be another tool in the arsenal against cancer, and benefit patients who don’t respond to current checkpoint inhibitors.
Michelle Petersen is the founder of Healthinnovations, having worked in the health and science industry for over 21 years, which includes tenure within the NHS and Oxford University. Healthinnovations is a publication that has reported on, influenced, and researched current and future innovations in health for the past decade.
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An avid campaigner in the fight against child sex abuse and trafficking, Michelle is a passionate humanist striving for a better quality of life for all humans by helping to provide traction for new technologies and techniques within healthcare.