BYU mentorship helps a PhD student overcome substantial health-related obstacles to graduate and leads to the successful publication of cancer research that identifies a new potential immunotherapy target.
Kiara Whitley (MMBIO ’22), recipient of the prestigious Simmons Cancer Center Fellowship, began her PhD in 2016. She joined the Weber Immunology Lab to study the function of the immune system’s T cells and their roles in fighting cancer. However, in the middle of her program, Whitley faced health challenges that threatened both her life and her studies. Rather than being overwhelmed by tremendous obstacles, Whitley used them to fuel her desire to complete her research, which identified new roles for a protein called CD5. These discoveries may open new avenues for treating cancers.
Cancer is a massive global health burden. According to the World Health Organization, cancer is responsible for approximately one in every six deaths, or ten million annual deaths worldwide. Although cancer remains a widespread and devastating disease, the American Association for Cancer Research reports that scientific advancements in cancer prevention, screening, and treatments have played a role in the observed 33 percent decrease in mortality rate from 1991 to 2020. As a part of these advancements, scientists have developed ways to use the body’s immune system to fight cancers, a technique called immunotherapy.
The immune system is a complex network of organs, cells, and proteins that defend the body against infection and damage. Typically, immune cells identify threats that can cause disease and will mount responses to eliminate these pathogens, which can be bacteria, viruses, and other substances. Unfortunately, there are gaps. Whitley says, “Cancers are sneaky and have developed ways to evade immune detection, which can result in the development of large tumors that can ultimately be life-threatening.”
The immune system is broken into two main branches: the innate and adaptive systems. General barriers such as skin and processes such as inflammation make up the innate system, the body’s first line of defense. The adaptive immune system, however, is more specific; it requires immune cells to differentiate foreign and harmful cells from the body’s cells and make extremely targeted attacks.
The Adaptive Immune System’s MVP
The Weber Lab focuses on helper T (Th) cells, which are, arguably, the most crucial part of the body’s adaptive immune system. “They orchestrate the immune system,” says Dr. Scott Weber (ZOO '00), professor of molecular biology and immunology.
Th cells are initially activated by binding to cells that present fragments of the pathogens or damaged cells the immune system needs to destroy. “Subsequently,” Weber says, “their interactions with other immune cells initiate a whole-body immune response, so you really don’t have an adaptive immune system without a good helper T cell.”
The cells interact with proteins on the surface of other body cells. These interactions tell the Th cells whether they should activate and initiate an immune response. When Th cells receive an activation signal, they begin to grow and divide, release inflammatory molecules, and recruit other immune cells to destroy the invaders or, in this case, cancerous cells. Activated Th cells also experience changes in metabolism to support these processes.
Tumors have developed several strategies to impair Th cell function and evade detection. They can place inhibitory proteins on the surface of their cells, and these proteins interact with Th cells to inhibit their activation. Additionally, the rapid growth of tumor cells can deplete nutrients (e.g., glucose) in their surroundings, which leaves little fuel for Th cells to function.
“Cancer cells suck up all the glucose from their environment,” explains Whitley. “Because activated T cells primarily rely on glucose metabolism for fuel, they go in to attack tumor cells but can’t function and literally come out exhausted.”
Research and Resilience
Before Whitley started her PhD research, the Weber lab identified a protein on the surface of Th cells called CD5, which inhibits Th cell activation, possibly through changes in metabolism. Whitley hypothesized that blocking or removing this protein would alter Th metabolism and lead to more powerful activation, which may be useful in fighting cancers.
Just as the study was coming together, Whitley was struck with life-altering health challenges that forced her to step away from the research.
“That was a really dark time, and I honestly thought I might die,” Whitley says. “I didn’t, thankfully, but it took about two years to feel like myself again and get back in the lab.”
That was a really dark time, and I honestly thought I might die. I didn’t, thankfully, but it took about two years to feel like myself again and get back in the lab.
Amazingly, Whitley did not give up on her research. As she slowly made her way back into the lab, she resumed her research on CD5 and its potential as an anti-cancer target in Th cells. Whitley and her research team collected Th cells from the spleens of two groups of mice: one with normal CD5 and one with no CD5. Next, they measured metabolism-related changes in the Th cells to see how getting rid of CD5 would alter their function.
Overall, the research team saw clear involvement of CD5 in regulating the metabolism of helper T cells.
“The research showed us that T cells are metabolically flexible,” says Whitley. “The Th cells from mice without CD5 took up more fuels, which, we think, may help them meet their metabolic needs even in a tumor environment that has limited nutrients.”
In other words, the Th cells with no CD5 were more metabolically active, which may make them more effective in fighting cancers.
Positive Signs in Clinical Trials
Currently, other Th cell proteins are targeted by immunotherapies in the clinic to promote Th cell activation and treat different cancers. The FDA has approved these immunotherapies to treat breast cancer, cervical cancer, Hodgkin lymphoma, lung cancer, stomach cancer, and others. The Weber Lab’s research has identified the CD5 protein as another potential drug target.
“In a clinical sense, the hope is that blocking these cancer cells from interacting with CD5 will change Th cell metabolism,” says Whitley. “Then Th cells can effectively go into the nutrient-depleted environment around tumors and still do their job.”
According to Weber, if Th cell metabolism can be ramped up through CD5 targeted therapy, it could be combined with other immunotherapies. The next step would be identifying antibodies or other tools that could potentially inhibit CD5. “There are a bunch of things we could pursue from here, but for now, we are hopeful CD5 becomes part of the anti-cancer conversation.”
More than a Mentor
Whitley explains that a large part of her success, despite her health, was due to her mentor, Dr. Weber. “The biggest thing for me was my advisor,” she recalls. “There’s no way I could have completed this project without his encouragement and support. He always told me he wanted me to succeed, and in the end, I did.”
Reflecting on Whitley’s PhD journey, Weber states: “She did it. This was definitely a success story of someone overcoming some real trials and hanging in there. She had grit and toughness and ultimately met the bar, something she should be extremely proud of.”
There’s no way I could have completed this project without [Dr. Weber's] support. He always told me he wanted me to succeed, and in the end, I did.
The BYU Simmons Center for Cancer Research is dedicated to training undergraduate and graduate students in experimental oncology to make a significant contribution to finding a cure for cancer. Each year, the center sponsors numerous cancer research fellows. These students are given the opportunity to perform full-time cancer research under the direction of their faculty mentor during spring and summer terms at BYU or abroad, and some students are sponsored for year-round research positions.
“During my rotation in the Weber Lab at the beginning of my PhD, I fell in love with Dr. Weber’s research. Since then, I’ve been happy in the lab because of the research focus, the lab environment, my lab mates, and Dr. Weber, who has been so supportive, encouraging, and kind.” Moreno’s dissertation research expands on Whitley’s, exploring the role of CD5 in inflammatory disease and cancer. He hopes to publish his findings in the near future.