by University of Melbourne
Melbourne researchers have identified a way
to improve the immune response in the face of severe viral infections.
It is widely known that 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.
A team from the Peter Doherty Institute of
Infection and Immunity (Doherty Institute) led by University of Melbourne's Dr.
Sarah Gabriel, Dr. Daniel Utzschneider and Professor Axel Kallies has been able
to identify why immune exhaustion occurs and how this may be overcome.
The team had previously identified that while
some T cells lost their function and became exhausted within days, others,
called Tpex cells, were 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,"
Professor Kallies said.
"While immunotherapy works really
well, it is only effective in around 30 percent 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."
In their most recent paper published today
in Immunity, the team has now identified a mechanism explaining how Tpex cells
can maintain their fitness over long periods.
Professor Kallies says that the discovery has
the potential to 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,"
Dr. Gabriel said.
"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."
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 this. We discovered that Tpex cells were exposed to
increased amounts of an immunosuppressive molecule, TGF-β 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.