From virology to immunology
“My adventure in science started on the day I took a virology class in university. It completely changed my life.”
A business student at that time, Dr. David Brooks did not expect that the virology class would put him on a totally different track. It marked the start of his life-long research career on the immune system and its failure to fight long-term chronic diseases, from viral infections to cancers.
“I was fascinated by viruses and how a small, non-living entity—that sometimes only has four genes—could completely commandeer a cell for its own purposes.” David recalls with excitement.
After completing his PhD at UCLA on how HIV hides from human immune responses, David realized that studying viruses only tells half of the story. He needed to understand the immune system better to see why it is outsmarted in chronic infections.
A concept called “T cell exhaustion” caught his attention.
T cell exhaustion happens when CD8+ T cells—a type of immune cells that can recognize and destroy cells infected by viruses, other pathogens, as well as cancer cells—no longer respond effectively after a long period of stimulation from binding to these harmful cells.
“T cell exhaustion is a natural response that our body has evolved to stop our immune system after T cells have presumably completed their job. However, in the case of certain cancers or chronic viral conditions, the immune system stops responding even though its job is not yet done.”
David delved into T cell exhaustion during his postdoctoral studies in Dr. Michael Oldstone's lab at The Scripps Research Institute. The team used a preclinical model infected with Lymphocytic Choriomeningitis Virus (LCMV) to probe the immune responses to the virus.
In a study published in Nature Medicine, David discovered that blocking IL10—a small protein produced by immune cells that suppresses immune functions—can prevent CD8+ T cell exhaustion during viral infection and lead to clearance of the otherwise chronic infection.
“This work sparked my interest in how cellular factors can signal T cell exhaustion, laying the foundation for the rest of my career.” David comments in retrospective.
Unveiling the mechanism of T cell exhaustion
David established his own lab at UCLA and continued investigating how IL10 contributes to T cell exhaustion. One day, one of his postdoctoral students, Dr. Elizabeth Wilson, suggested: “Since type 1 interferon (IFN-I) can induce IL10, why not block interferon and see if it improves immunity against viruses?”
David was skeptical at first, as interferons are proteins known for disrupting viral replication and activating immune cells. “Removing an anti-viral system will not help in fighting a viral infection.” David predicted at that time.
Surprisingly, experiments showed that without IFN-I, the viral infection in LCMV models not only showed no signs of getting worse but it was actually eliminated within a few weeks.
“This was one of our most significant observations,” says David, “it showed a very different effect of interferons, completely contrary to what was known to the field.”
Through these studies, the team found that the immune system uses type 1 interferons to gauge how well it is fighting an infection. More interferons indicate more viruses present. When interferons are completely removed, this essentially gives immune cells an ‘inflammatory holiday’ and enables them to take a break from responding to inflammation signals. These cells can then regroup and revert into a state where they are better equipped to fight infection (published in Science).
Overcoming exhausted T cells in cancer
T cell exhaustion is also seen in cancer.
“There are many cancers that behave like chronic viral infections,” David comments. “They constantly stimulate the immune system to respond, which can lead to T-cell exhaustion.”
David moved his lab to the Princess Margaret Cancer Centre in 2015 to study T cell exhaustion in human tumour models. Knowing that interferons can both drive and suppress immune responses, David’s next step was to determine their role in cancer.
“We found that while interferons can provide necessary anti-cancer signal on T cells, when this signal is prolonged, T cells become exhausted and lose their ability to fight tumours,” says David. “This switch to suppression is particularly devastating because it underlies the failure of multiple types of otherwise highly effective therapies.”
So how do the signals produced by interferons switch from good to bad?
Dr. Sabelo Lukhele, a Postdoctoral Researcher in David’s lab, looked at T cells in the tumor microenvironment and observed a spike of a protein called IRF2 in response to sustained interferon signaling. The team found that after interferons send signals to T cells, cellular protein IRF2 increases to regulate genes that dim the immune function of the cell. They shut down IRF2, which gave the immune system a boost right when it started to lag in the fight against cancer (published on Immunity).
“We found that IRF2 is the switch that turns positive responses in T cells to a negative, suppressive one,” says David excitedly. “Reversing this allowed T cells to retain their function and control tumour growth in pre-clinical models.”
To turn off this immunosuppressive switch, David’s team innovatively designed CAR T cells with the IRF2 protein removed to prolong the effectiveness of the therapy. CAR T cells are essentially engineered T cells with surface receptors that specifically target cancer cells, enhancing their anti-cancer capabilities.
“We think that removing IRF2 will enable CAR T cells to finish the job of killing the cancer,” says David. “This new approach has been patented and we are currently testing it in pre-clinical studies with the hope of moving it into the clinic in the future.”
Predicting the effect of immunotherapy
In addition to developing new therapies, David’s research on interferon also sheds light on the effectiveness of existing cancer treatments.
When a patient’s T cells have a strong reaction to interferons, the patient is unlikely to respond well to anti-PD-1, a type of immunotherapy. On the other hand, those that react weakly to interferons have a better outcome for the therapy. David’s team published this observation in Nature Immunology, showing the predictive power of interferons.
“A key challenge in cancer treatment is predicting how patients will respond to specific therapies. This will allow us to find alternative options for those who do not respond well.” David adds.
David’s team is exploring the use of interferon signaling as a biomarker to predict how cancer patients will respond to immunotherapy. This innovative strategy, recently patented and under development at the Princess Margaret, aims to guide therapeutic decisions in clinical settings.
“We want to get the right therapy to the right people,” David asserts, expressing hope that this approach will make that possible.
New science, new hopes
“It was a humbling experience jumping from virology to immunology and from studying viral infection to studying cancer; there was so much to learn.”
For David, it is the intellectual stimulation and the opportunity to help cancer patients that drive him every day to advance in research.
“The questions we ask each day are new. The things we uncover each day are new,” says David. “One of the great things about science is that it offers endless opportunities to deepen our understanding of biology and leverage that knowledge to combat disease.”
Meet PMResearch is a story series that features Princess Margaret researchers. It showcases the research of world-class scientists, as well as their passions and interests in career and life—from hobbies and avocations to career trajectories and life philosophies. The researchers that we select are relevant to advocacy/awareness initiatives or have recently received awards or published papers. We are also showcasing the diversity of our staff in keeping with UHN themes and priorities.