Melbourne researchers say they have identified a way to improve the immune response in the face of severe viral infections.

Severe viral infections and cancer cause impairments to the immune system, including to T cells, a process called immune ‘exhaustion’. 

Overcoming immune exhaustion is a major goal for the development of new therapies for cancer or severe viral infections.

In new studies, researchers have been able to identify why immune exhaustion occurs and how this may be overcome.

While some T cells lose their function and become exhausted within days, others, called Tpex cells, are able to maintain their function for a long period of time.

“This idea that you need to overcome exhaustion and make T cells better is at the heart of immunotherapy,” says researcher Dr Axel 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 team has now identified a mechanism explaining how Tpex cells can maintain their fitness over long periods, which Professor Kallies says could improve the success rate of immunotherapy.

“We found that activity of mTOR, a nutrient sensor that coordinates cellular energy production and expenditure, is reduced in Tpex cells compared to those which were becoming exhausted,” said the University of Melbourne’s Dr Sarah Gabriel.

“What this means is that Tpex cells were able to dampen their activity so they could remain functional longer – it’s like going slower to have the endurance to run a marathon instead of a sprint at full speed.”

Fellow researcher Dr Daniel Utzschneider stressed that flicking this switch to the immune system is a balancing act.

“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,” Dr Utzschneider said.

“The next step was finding the mechanism which was enabling this. 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.”

Excitingly, the researchers were able to use this discovery to improve the immune response to severe viral infection.

“When we treated mice with an mTOR inhibitor early, this resulted in a better immune response later during the infection,” Dr Gabriel said.

“In addition, mice that had been treated with the mTOR inhibitor responded better to checkpoint inhibition, a therapy widely used in cancer patients.”

The team will now explore this mechanism in preclinical cancer models.