Growing up in Qingdao, a coastal city in China, Dr. Yanpu He fell in love with windsurfing
A modern innovation of traditional water sports, windsurfing as we know it today was conceptualized and designed by engineers who wanted to develop a more accessible, cost-effective way to enjoy sailing. Controlled by a boom, mast and fin, the sport requires balance, quick reflexes to adapt to ever-changing wind and water conditions, along with focus, good technique, and endurance; skills, one might argue, that are equally important for researchers of the biomedical sciences.
“Research is a marathon,” Dr. He confirms. “While I spend most of my time in the lab, you will also find me out on the water. Windsurfing keeps me physically and mentally healthy; it’s a sport I really enjoy and one that I want to keep doing the rest of my life.”
When Dr. He received his acceptance to the doctoral program and, later, the postdoctoral fellowship at Massachusetts Institute of Technology (MIT)—which sits on the banks of the Charles River in Boston, USA—he would not only be able to revisit his love of windsurfing, he would find the perfect incubator for his inclination to interdisciplinarity and his dream of contributing to a cure for cancer.
“While at MIT, I discovered the newly built Koch Institute for Integrative Cancer Research,” he recalls. “At the time, I didn’t think that it would be possible for me to be a part of this Institute because I was not a biology major. I had studied chemical engineering and mathematics; I was a typical engineer. But their ethos—of bringing engineers, clinicians, and biologists together—gave me the opportunity and introduced me to cancer research. My experience there made me want to continue this collaborative mode of research. I can see the benefits of bringing people with different expertise together. I think it can spark new ideas and create translational innovations.”
Dr. He and his collaborators within the labs of Dr. Paula Hammond, Dr. Darrell Irvine, and Dr. Angela Belcher would demonstrate the particular power of interdisciplinarity when they engineered a novel vaccine from a protein found in the body and demonstrated its effectiveness in not only eliminating colon and skin cancer tumours in mouse models, but also preventing their recurrence, harnessing the body’s own immune cells.
This important discovery did not emerge overnight. Dr. He had to overcome a number of key hurdles along the way, including how to engineer a therapy that would be effective for people with immunodeficiencies.
In a talk given at UBC in February 2024, he highlighted this critical challenge his research aims to address: “Our immune system is sometimes damaged or weakened by aging, genetic defects, or by the disease itself. With a broken immune system, even if we get the vaccine into our body, at the right place and time, we cannot activate the desirable immune response.”
Dr. He has focused his early research on how to address individual differences in immune system function by exploring the untapped potential of the Stimulator of Interferon Genes (STING) signaling pathway, a key therapeutic target for eliminating cancer cells that was discovered within the first decade of the 2000s.
“People are rapidly realizing how important this (STING) signaling pathway is and how promising it is as a therapeutic target.”
The STING pathway is activated when double-stranded DNA, which is typically confined to a cell’s nucleus, is detected in the cytosol, signaling the presence of a microbial infection or tissue damage. This triggers the production of a small molecule messenger, called cGAMP, which binds to an intracellular protein called STING. The binding initiates a cascade of events, culminating in the activation of immune responses to neutralize the threat. Most of the current STING-targeted therapies rely on delivering cGAMP to activate this pathway.
However, these existing therapies face two significant challenges. First, approximately 20% of the human population carries a mutation in the STING protein that severely compromises its signaling function, rendering cGAMP delivery ineffective due to the lack of a functional receptor. Second, cancer cells can evolve treatment resistance to evade immune detection by epigenetically silencing their immuno-receptors, effectively blocking the pathogen-sensing signals needed to make them visibleto immune cells. As Dr. He explains, “Fighting cancer is really fighting an evolution problem.”
To address these hurdles, Dr. He and his collaborators set out to engineer a solution that bypasses the reliance on naturally occurring STING receptors. Their approach began by tracing the 600-million-year evolutionary history of the STING protein. They focused on a key feature of STING, a characteristic core structure that forms a tetramer, which has been preserved across species—from the STING of bacteria to that of anemone, oysters, chickens, all the way to human STING.
Building on this insight, they engineered a truncated version of the protein, called STINGΔTM. By pre-assembling this truncated protein with cGAMP, they created a well-defined tetramer complex resembling its ancestral forms. When delivered into cells with impaired STING function, the cGAMP-STINGTM complex successfully restored signaling, even in cases where state- of-the-art cGAMP delivery therapies failed.
But when they tried to publish their results, reviewers were critical. At the time, seminal studies had demonstrated that STING signaling requires its transmembrane domain (TM), which they had removed, to interact with various cellular membranes. They wanted Dr. He and his collaborators to dig deeper, to account for their success in activating STING signaling when so many others had failed. The reviewers wanted to know what made this engineered protein complex different.
Undaunted, Dr. He and his collaborators created cell lines for the versions of STING that arise in the human population and discovered that their success depends on the pre-assembly of the signaling complex prior to delivery. The engineered protein complex (STINGΔTM) must be bound to the small molecule messenger (cGAMP) before it enters the cell.
In all cases, the introduction of STINGΔTM-cGAMP to the cell lines helped restore the signaling activity needed to alert the cells to the health threat. What’s more, they learned that STINGΔTM-cGAMP bypasses natural signaling pathways, effectively creating its own way to get the message across.
This discovery would put a feather in the cap of his doctoral work. Even so, Dr. He was not satisfied; he knew he could achieve more. “I didn’t want to just recognize the cancer cells, I wanted to be able to eliminate them,” he recalls.
His postdoctoral fellowship would provide him with an opportunity to shift his talent and energy towards the treatment of solid tumors.
Researchers have established that there are two types of cells that kill malignant cells. “Natural Killer cells and CD8+ T cells are a good crime-fighting duo,” Dr. He explains. Their effectiveness is regulated by CD4+ T cells and putting a restraint on the killer cells is critical for our health. Dr. He explains. “They are the main reason more people don’t live with autoimmune diseases.”
But to rid the body of cancer cells, CD4+ T cells need to be temporarily activated to become Type 1 Helper (TH1) cells, to help unlock the seek-and-destroy power of the killer duo cells. So, Dr. He paired a smaller version of an immune checkpoint blockade antibody (a nanobody) to his STINGΔTM+cGAMP platform. He hypothesized that this nanobody would effectively block the cancer cell’s ability to disguise itself from the immune cells. The hoped for result—to enable the immune cell to recognize the cancer threat, via STING activation, and eliminate it by unleashing the killer duo cells.
Dr. He and his team tested the compound on preclinical tumour models and discovered that their protein complex could not only activate the immune cells (CD8+ T cells, NK cells, and CD4+ T cells) to completely eliminate the cancer cells, but could also prevent cancer recurrence.In short, the test subjects were effectively vaccinated against this type of cancer.
In the process, they also discovered more about the specific actions of each immune cell. While NK cells inhibit tumour growth early on, CD8+ T cells pick up the effort in the later stages. They also observed that the addition of cGAMP to the nanobody-infused STINGΔTM complex polarized the CD4+ T cells towards an immunostimulatory type, helping immune cells to kill cancer cells.
“In our experiments, CD4+ T cells played an even more important role than CD+ T cells. We were not expecting that at all.”
“This really opens up opportunities for us to develop drug interventions to control the fate and purpose of CD4+ T cells, to tune them towards their beneficial characteristics to really leverage their therapeutic potential,” Dr. He shares. Precisely how the CD4+ T cells were converted to this TH1 helper form through STING activation is a question he plans to pursue in future studies.
These findings are especially important, Dr. He points out, when we realize that the number of CD8+ T cells decrease as we age, along with their cancer-fighting protection, unlike CD4+ T cells, which are sustained across the human life span. “There is a lot of plasticity. We can polarize them back and forth,” Dr. He explained in his February talk. “I think that really opens up opportunities for us to develop drug interventions to control the fate and purpose of CD4+ T cells—tune them towards the beneficial aspect to really leverage their therapeutic potential to help elderly cancer patients.”
As he sets up his lab in the newly built SBME building at UBC, Dr. He is eager to apply what he’s learned about the immune system, and the biotechnology he has developed, to a wider array of diseases and disorders.
“I believe this approach—understanding the immune pathway and designing the relevant signaling complex to restore signaling—can be extended to many other immunodeficiencies,” he shares.
He looks forward to collaborating with UBC experts like Drs. Kelly McNagny, Nika Shakiba, Nozomu Yachie, Carolina Tropini, Megan Levings, and Peter Zandstra to explore the far-reaching possibilities in the fields of stem cell biology, microbiota-immune cell crosstalk, and cellular lineage tracing. “There are so many amazing researchers whom I want to learn from and work with here at UBC. I think we can develop good synergy, pooling our knowledge to engineer great immunotherapies.”