Harnessing the human body’s power to combat cancer is all in a day’s work for University of Wisconsin–Madison postdoctoral research associate, Portia Smith, PhD. Whether she is engineering white blood cells to fight tumors or exploring the mechanisms behind the deadliest forms of cancer, Smith is determined to help the human immune system win the battle against cancer.
As a PhD candidate in the lab of UW–Madison Stem Cell and Regenerative Medicine Center (SCRMC) member, Igor I Slukvin, MD, PhD, Smith began to explore immunotherapy, which is a type of treatment that uses the patient’s own immune system to fight cancer cells, but her interest in this area goes back to her very first immunology course as an undergraduate.
“Science has been such a passion of mine throughout life, but I became really interested in immunology because it was like a whole other world that was unveiled to me, yet it had existed at the microscopic level the entire time” says Smith who earned a bachelor’s degree in integrated biological sciences at the University of Vermont. “I was a part of several different labs doing undergraduate research and that’s where I developed my spark to pursue scientific research and do a PhD.”
Smith says UW–Madison was her top choice for graduate school, and she was thrilled to be accepted to the Comparative Biomedical Sciences program through the School of Veterinary Medicine.
“Igor and I had an interview prior to me becoming a direct admit and from that one conversation, we learned it was a great fit as I was interested in translational immunology research, and he was looking for someone to pursue that project,” says Smith.
She began working with Slukvin to engineer macrophages, a type of white blood cells, from human induced pluripotent stem cells (iPSCs) to treat solid tumor cancers. She did this by genetically modifying targets of inhibitory pathways within the tumor microenvironment using CRISPR/Cas9 gene editing.
“Macrophages possess these incredible mechanisms to survey the body and phagocytose [‘eat’ and destroy] foreign pathogens, detect cancerous or dying cells, and clear them out of our tissues. My project heavily focused on harnessing these mechanisms performed by macrophages, but direct them towards killing solid tumors,” says Smith. “In order to do that, we introduce our desired genetic modifications into the stem cells using CRISPR/Cas9 gene editing, which gives us an unlimited source of starting material. From there, we use a highly specified protocol, developed in the Slukvin Lab, called ‘in vitro hematopoiesis’, that essentially means generating blood cells [and macrophages] from stem cells in a petri dish. To take it one level more specific, we were targeting the “eat me”/ “don’t eat me” molecular pathways that cancer cells upregulate to avoid being “eaten” or phagocytosed by macrophages.”
Tumor cells find multiple ways to evade the immune system, and one of those ways is to convince the immune system that they are healthy cells (i.e. “don’t eat me”). They do this is by upregulating, or increasing, don’t eat me receptors, one of which is known as CD47. Smith explained that when the tumor up regulates CD47 it tells the macrophage, “Hey, I’m normal, don’t eat me,” which prevents those macrophages from attacking cancer. As such, Smith and the Slukvin lab worked to alter the macrophages to evade this mechanism.
In researching ways to avoid the “don’t eat me” signal, they discovered in literature review that macrophages have a receptor called SIRPalpha (SIRPα), which recognizes CD47. So, Smith began focusing on genetically “knocking-out” or deleting SIRPα, so the macrophages would no longer detect the “don’t eat me” signal from cancer cells. In her own hands, she also found that by deleting SIRPα, the macrophages are protected from what’s called macrophage exhaustion, and they were able to continually kill the tumor, when macrophages that contained SIRPα, could not.
“Essentially, we’re engineering these macrophages to be able to detect and kill the tumor better,” says Smith.
This novel research will be published soon, and has already received positive recognition for her efforts, willing the Young Investigator’s Abstract Travel Award at the Society for Immunotherapy of Cancer (SITC) 39th Annual Meeting in Houston, TX in November 2024. While Smith is grateful to have been a part of this work, Slukvin is equally grateful for Smith’s contributions.
“After joining my lab, Portia embraced a novel project to develop adoptive cell therapies for cancers that are difficult to treat,” says Slukvin, who is the first Henry Pitot Professor of Pathology and Laboratory Medicine, a Professor of Cell and Regenerative Biology, and Co-Director of Precision Medicine and Genomic Resources at the Wisconsin National Primate Research Center. “Portia is a gifted and highly dedicated young scientist. Her persistence and effort were essential for the successful completion of her high-impact research project.”
While her study with Slukvin may be complete, Smith knows there is more exploring to do, so after graduating in December 2024, she decided to continue her postgraduate work at UW–Madison.
“Working at the University has been such a pleasure because it fosters collaboration so well,” says Smith. “Being in an interdisciplinary lab, as we are simultaneously researching hematology, stem cells, and now immunotherapies, I have had the opportunity to work with several other labs on campus which only furthers creativity and learning skills outside your wheelhouse. That type of collaborative research environment is incredibly rewarding to work in.”
As a postdoctoral research associate Smith is continuing her work with immunotherapy, focusing on creating chimeric antigen receptor (CAR) T cells (specialized white blood cells) engineered to target multiple tumor antigens in pediatric high-grade gliomas (HGGs), a group of aggressive brain tumors. She is currently working in the lab of SCRMC member, Christian Capitini, MD, who also serves as Acting Director of the Carbone Cancer Center, the Jean R. Finley Professor in Pediatric Hematology and Oncology, a Professor of Pediatrics, and Chief in the Division of Hematology, Oncology, and Bone Marrow Transplant.
“Pediatric high-grade gliomas (HGGs), including diffuse intrinsic pontine glioma (DIPG) and glioblastoma (GBM), continue to have a poor prognosis with near 100% mortality,” says Capitini. “Traditional approaches, including surgery, radiation, and chemotherapy, offer limited hope. However, the discovery in 2018 that the diasialoganglioside GD2 is highly expressed on DIPG and GBM has driven renewed interest in chimeric antigen receptor (CAR) T cells. Dr. Smith’s project focuses on creating CAR T cells engineered to target multiple tumor antigens, including GD2, with the hope of offering a novel approach to treat pediatric HGGs.”
While Smith is still new to the lab, she is thrilled to continue her efforts to harness the human immune system in the fight against cancer. She hopes that she can continue conducting immunotherapy research for years to come and that these novel studies will lead to an improved prognosis for patients in the future.
“All of these processes and super complex systems have evolved over hundreds of millions of years to protect your body from foreign pathogens and invaders. The body contains these incredibly intricate mechanisms that are protecting itself, and it’s just the normal ‘default mode’,” says Smith. “I think the more I learn, the more I want to know, and it becomes an endless tunnel of information that you can just tumble down. To me, learning about the body’s own immunological processes is one of the best tools we have to fight cancer, and researching ways to harness that power has been incredibly rewarding.”