Control of immune response relies on a key protein, study finds
HealtyScientists have identified a protein that appears to play a key role in controlling immune response. By testing how the protein works in mice, they found possible explanations for why immune T cells sometimes fail to eliminate tumors and chronic infections. They suggest the discovery may lead to new treatments for many diseases, including cancer, autoimmune diseases, and infections.
The study, led by Sanford Burnham Prebys Medical Discovery Institute (SBP) in La Jolla, CA, is published in the journal Immunity.
Senior author Linda Bradley, a professor in SBP's Immunity and Pathogenesis Program, says:
"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. 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 researchers were interested in studying T cells because there is evidence many diseases - including infections and cancer - may arise because of problems with T-cell response.
T cells recognize and destroy specific invaders, including infectious bacteria and viruses from outside the body and rogue cells from inside the body that can trigger tumors.
T-cell activity is highly sensitive to control signals from other immune cells. These adjust T-cell response according to the nature of the "invasion." However, sometimes the response fails - for example, chronic viruses and cancers are able to escape attack by the immune system by disrupting T-cell response.
'Crucial for limiting immune responses'
One reason the T-cell response fails is because the cancer cells or viruses are able to use "checkpoints" on the T cells that turn down their activity - effectively exploiting a natural brake on the T cells. The checkpoints are normally controlled by patrolling immune cells and ensure T cells do not overreact and attack healthy tissue.
New drugs called "checkpoint inhibitors" - because they remove the brakes on the T cells - are beginning to show promise in treating some cancers. These drugs could potentially extend survival by years in the case of lung cancer and melanoma, note the authors.
From tests on mice, Prof. Bradley and colleagues found PSGL-1 plays a key role in inhibiting T-cell activity. It is needed to increase levels of checkpoints.
In mice bred to lack the protein, T cells remained active for longer than normal and completely eradicated lymphocytic choriomeningitis virus (LCMV) infections, which normally last months.
"Total clearance of LCMV is rare," Prof. Bradley notes. "When we saw that, we knew PSGL-1 was crucial for limiting immune responses."
When they injected the same mice with melanoma cells, the researchers found the resulting tumors grew more slowly than normal, suggesting PSGL-1 regulates T-cell responses in general.
Prof. Bradley suggests blocking the protein could boost the immune response to cancer and chronic viral infections like hepatitis. Alternatively, increasing the protein could inhibit immune response, an approach that could be useful for treating autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, psoriasis, and lupus.
"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."
Prof. Linda Bradley
The team at SBP is now looking at how the protein target might work with other anti-cancer drugs. T-cells do not reach all tumor cells, so an immunotherapy based on PSGL-1 could be more effective when combined with drugs that kill cancer more directly - and vice versa.
The study, led by Sanford Burnham Prebys Medical Discovery Institute (SBP) in La Jolla, CA, is published in the journal Immunity.
Senior author Linda Bradley, a professor in SBP's Immunity and Pathogenesis Program, says:
"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. 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 researchers were interested in studying T cells because there is evidence many diseases - including infections and cancer - may arise because of problems with T-cell response.
T cells recognize and destroy specific invaders, including infectious bacteria and viruses from outside the body and rogue cells from inside the body that can trigger tumors.
T-cell activity is highly sensitive to control signals from other immune cells. These adjust T-cell response according to the nature of the "invasion." However, sometimes the response fails - for example, chronic viruses and cancers are able to escape attack by the immune system by disrupting T-cell response.
'Crucial for limiting immune responses'
One reason the T-cell response fails is because the cancer cells or viruses are able to use "checkpoints" on the T cells that turn down their activity - effectively exploiting a natural brake on the T cells. The checkpoints are normally controlled by patrolling immune cells and ensure T cells do not overreact and attack healthy tissue.
New drugs called "checkpoint inhibitors" - because they remove the brakes on the T cells - are beginning to show promise in treating some cancers. These drugs could potentially extend survival by years in the case of lung cancer and melanoma, note the authors.
From tests on mice, Prof. Bradley and colleagues found PSGL-1 plays a key role in inhibiting T-cell activity. It is needed to increase levels of checkpoints.
In mice bred to lack the protein, T cells remained active for longer than normal and completely eradicated lymphocytic choriomeningitis virus (LCMV) infections, which normally last months.
"Total clearance of LCMV is rare," Prof. Bradley notes. "When we saw that, we knew PSGL-1 was crucial for limiting immune responses."
When they injected the same mice with melanoma cells, the researchers found the resulting tumors grew more slowly than normal, suggesting PSGL-1 regulates T-cell responses in general.
Prof. Bradley suggests blocking the protein could boost the immune response to cancer and chronic viral infections like hepatitis. Alternatively, increasing the protein could inhibit immune response, an approach that could be useful for treating autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, psoriasis, and lupus.
"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."
Prof. Linda Bradley
The team at SBP is now looking at how the protein target might work with other anti-cancer drugs. T-cells do not reach all tumor cells, so an immunotherapy based on PSGL-1 could be more effective when combined with drugs that kill cancer more directly - and vice versa.
