An impressive new study from a team of Australian researchers has identified the novel mechanism behind immune exhaustion. The findings point to a treatment method that could improve the success of cancer immunotherapy and help patients beat back severe viral infections.
Immune exhaustion is a condition where immune T cells become progressively dysfunctional and ineffective. It’s often seen in cancer patients or during chronic viral infections. Axel Kallies, a researcher working on the project from the Peter Doherty Institute of Infection and Immunity, says understanding why some immune cells become “exhausted” is vital to developing effective cancer immunotherapies.
“This idea that you need to overcome exhaustion and make T cells better is at the heart of immunotherapy,” explains Kallies. “While immunotherapy works really well, it is only effective in around 30 per cent of people. By discovering a way to prime T cells differently so they can work efficiently in the long run, we may be able to make immunotherapy more effective in more people.”
The first part of the research looked at a specific kind of immune cell, called Tpex cells. These cells are like the marathon runners of immune cells. They effectively maintain function over a long period of time and the researchers wanted to understand how they did that.
It was discovered that the difference between Tpex cells and other more easily exhausted T cells is a signaling protein called mTOR. Tpex cells were seen to have lower mTOR activity, suggesting this mechanism was the way in which the immune cells dampened their activity.
“The next step was finding the mechanism which was enabling this,” says Daniel Utzschneider, another researcher working on the project. "We discovered that Tpex cells were exposed to increased amounts of an immunosuppressive molecule, TGFb, early on in an infection. This molecule essentially acts as a brake, reducing the activity of mTOR and thereby dampening the immune response.”
The final part of the research explored inhibiting mTOR activity in mouse models. The promising results revealed immune responses against severe viral infections were enhanced when the animals were treated with a mTOR inhibitor.
“In addition, mice that had been treated with the mTOR inhibitor responded better to checkpoint inhibition, a therapy widely used in cancer patients,” notes Sarah Gabriel, from the University of Melbourne.
Plenty more work is needed to understand this new discovered mechanism before the findings can lead to clinical treatments. The first step will be to specifically explore the effects of this kind of mTOR inhibition in preclinical cancer models.
Hypothetically, this exciting immune discovery could lead to new therapies for patients suffering severe viral infections. However, Utzschneider is careful in stressing they will need to be cautious in tinkering with this immune switch in humans. Turning up, or turning down, immune system activity needs to be done with great care so as not to generate adverse health effects.
“You don’t want to dampen the response too much to the point the response becomes ineffective – you don’t want to be left walking the race,” says Utzschneider.
The new study was published in the journal Immunity.
Source: Doherty Institute