Researchers at Sanford-Burnham Prebys Medical Discovery Institute discovered an immune factor regulating T-cell checkpoints. Mice lacking the molecule, called PSGL-1, had more effective immune responses against both infections and cancer — findings that advance the understanding of why immune T-cells fail to conquer chronic infections or tumors.
“We discovered that a protein on the surface of T cells, P-selectin glycoprotein ligand-1 (PSGL-1), acts as a negative regulator of T cell function,” said Linda Bradley, a professor in the Immunity and Pathogenesis Program at SBP. “PSGL-1 has the broad capacity to dampen T cell signals and promote the exhaustion of T cells in viral and tumor mouse models.”
The molecule is related to what is known as checkpoint inhibition, meaning the presence of factors on the surfaces of T-cells that work as brakes, preventing a full-blown immune response from taking place. Drugs acting on these checkpoint inhibitors are used in cancer treatment, allowing the brakes to be released to unleash a fierce immune response that can target tumors.
Such drugs have shown remarkable efficacy in several cancer forms. But the researchers, using mice lacking PSGL-1, discovered that the factor is needed to increase the levels of checkpoints on T-cell surfaces. Without this immune factor, there are no brakes.
“Blocking PSGL-1 may enhance the immune response to cancer and chronic viral infections such as hepatitis. 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,” said Bradley.
The mice in Bradley’s study had been infected with lymphocytic choriomeningitis virus (LCMV), an infection that tends to become chronic. The study, which was published in the journal Immunity, showed that mice lacking PSGL-1 completely wiped out the infection. “Total clearance of LCMV is rare,” Bradley said. “When we saw that, we knew PSGL-1 was crucial for limiting immune responses.”
Since immune checkpoints are crucial for tumors to evade the immune system, the team then explored the consequences of a PSGL-1 lack in mice who received melanoma cells. As suspected, tumors in mice lacking the immune factor grew slower than in normal mice.
The publication of the study, “PSGL-1 Is an Immune Checkpoint Regulator that Promotes T Cell Exhaustion,” has led to a rush among commercial stakeholders. “We’ve received a lot of interest from pharmaceutical companies wanting to explore the clinical potential of our findings,” said Bradley, adding that “PSGL-1 inhibitors could provide another tool in the arsenal against cancer, and benefit the many patients who don’t respond to the currently available checkpoint inhibitors.”
The research team is now exploring if drugs blocking PSGL-1 might be used together with other cancer treatments to further improve the efficiency of a potential drug.
We are sorry that this post was not useful for you!
Let us improve this post!
Tell us how we can improve this post?