Priming our immune system for the marathon of severe disease

Overcoming immune exhaustion - the impairments to the immune system that is caused by severe disease - is the major goal for new therapies to treat cancer or chronic viral infections. Now researchers have identified how immune exhaustion occurs and successfully used their discovery to improve the immune response. 

people running on road during daytime

When our bodies are exposed to severe viral infections and disease, the race to combat infection is sometimes just too long. The immune system fights so hard that it wears itself out before the race is over. 

Known as immune exhaustion, it’s a phenomenon that is often seen in cancer patients – and can affect the entire immune system, but mainly an immune cell population called T cells, which play a critical role by killing cancer cells or cells infected by a virus.  

Overcoming immune exhaustion is the holy grail of cancer immunotherapy, including so called checkpoint inhibitor therapy. 

A team of Doherty Institute researchers led by University of Melbourne’s Dr Sarah Gabriel, Dr Daniel Utzschneider and Professor Axel Kallies identified why and how immune exhaustion occurs taking us one step closer to developing therapies to combat these illnesses.  

The team had previously identified that while some T cells lost their function and became exhausted, there were specific ones, called Tpex cells, that were able to maintain their function for a long period of time. 

This was an important discovery, as it turned out that Tpex cells are the ones that can be activated in immune therapy and subsequently kill tumor cells. 

Understanding immune exhaustion has been something Professor Kallies has been pursuing since 2014.  

“Back then we didn’t really know how T cells respond to tumour cells. We were looking at T cell responses to B cell lymphoma, and observed an unusual population of T cells that sparked our interest,” explains Professor Kallies.  

“But we were in the dark, we didn't quite understand, the details of the T cell response that we were looking at.

“The eureka moment came in 2016, through the work of the Kallies group and other researchers around the world, when it became clear there was an entity – the Tpex population – that played a key role in the process.

“That discovery revolutionised the field because it allowed us to very specifically study, in a very targeted manner, what it is that maintains a T cell response and allows checkpoint inhibitors to work.” 

In a study published in the leading immunology journal Immunity, the researchers refined their studies even further, identifying a mechanism that explains how Tpex cells were able to go the distance and become functionally superior. 

“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,” Dr Gabriel says. 

“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.” 

Professor Kallies says that the discovery has the potential to improve the success rate of immunotherapy. 

“This idea that you need to overcome exhaustion and make T cells better is at the heart of immunotherapy,” Professor Kallies says. 

“While immunotherapy works really well in some patients, it is only effective in around 30 per cent of people. By discovering a way to engage T cells differently so they can work efficiently in the long run, we may be able to make immunotherapy more effective in more people.” 

Burkitt's lymphoma cells, a cancer of the lymphatic system, monoclonal B-cell tumor, 3D illustration
Acute lymphoblastic leukemia, bone marrow smear, 3D illustration
Destruction of lymphoblasts. Conceptual 3D illustration of treatment of acute lymphoblastic leukemia

Dr 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 the mTOR activity to slow.  

“We discovered that Tpex cells were exposed to increased amounts of an immunosuppressive molecule, TGFb, early on in an infection,” Dr Utzschneider said. 

“This molecule essentially acts as a brake, reducing the activity of mTOR and thereby dampening the immune response.” 

Graphical abstract

Graphical abstract

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 have since conducted further research, which they believe will lead them to be able to even more precisely pinpoint which cells are responsible.   

This work was done in collaboration with researchers from the Olivia Newton John Cancer Research Institute and Monash University