A research team has developed immune cells equipped with a light-activated switch that adjusts protein functions and influences cell behavior. Under blue light exposure, these cells alter their shape, enabling them to invade laboratory-grown solid tumors and destroy them.
Immunotherapies that utilize a patient’s immune system to combat cancer have become a key treatment strategy. Although therapies like CAR T-cell treatment have shown positive results in conditions such as leukemias and lymphomas, their efficacy in solid tumors has not been as strong.
A group of scientists from the Penn State College of Medicine has successfully modified immune cells to enhance their ability to penetrate and eliminate solid tumors cultivated in laboratories. They devised a light-responsive mechanism that regulates protein functions related to cell structure and shape, which they integrated into natural killer (NK) cells—immune cells tasked with fighting infections and tumors. When subjected to blue light, these NK cells change their shape and are capable of infiltrating tumor spheroids, which are 3D tumor models created from mouse or human cells, ultimately leading to the destruction of cancerous cells. This innovative method holds promise for advancing cell-based immunotherapies, according to the researchers.
The results of this study will be published on October 25 in the Proceedings of the National Academy of Sciences. The team has also initiated the process of patenting the described technology.
“This technology is truly groundbreaking. While it shares similarities with CAR T-cell therapy, its key aspect is the ability of the cells to penetrate the tumor,” explained Nikolay Dokholyan, senior author of the study, G. Thomas Passananti Professor at the Penn State College of Medicine, and professor of biochemistry and molecular biology. “I am not aware of any other approach comparable to this.”
Initially approved by the Food and Drug Administration in 2017, CAR T-cell therapy has yielded positive outcomes for certain cancers, primarily hematological malignancies. This therapy involves extracting T-cells—white blood cells involved in the immune response—from patients and modifying them to express a protein that targets cancer cell proteins. Once reintroduced into the patient, these CAR T-cells effectively target and eliminate cancer cells that bear the specific proteins.
Nonetheless, CAR T-cell therapy has shown limited success in treating solid tumors, which account for about 90% of adult human cancers and 40% of pediatric cancers, according to Dokholyan. Immune cells struggle to penetrate dense protein and cellular networks surrounding these tumors, and the hostile tumor microenvironment undermines their cancer-fighting capabilities. Additionally, the significant heterogeneity among solid tumors complicates the identification of a distinct target protein for attack. Dokholyan noted that to enhance cell-based immunotherapies for solid tumors, it is crucial for immune cells to circumvent the tumor’s defenses.
The research team utilized computational modeling to design and evaluate a light-regulated version of septin-7, an essential protein for maintaining a cell’s cytoskeleton, which is responsible for cell shape and organization. They incorporated a light-sensitive element into septin-7, creating what Dokholyan referred to as “an allosteric regulator.” This light-responsive segment is positioned away from the protein’s active site, allowing the protein to function normally until activated by blue light, which toggles its function on or off.
The researchers then modified human NK cells with this light-sensitive septin-7 protein. Under blue light, they observed that the normal function of septin-7 was altered. The cells transformed into a more elongated, spindle-like configuration with increased protrusions, enabling them to engage with their surroundings and move effectively.
“Despite their small size of about 10 micrometers, when the protein is activated by blue light, NK cells reshape and can fit through openings as tiny as three micrometers. This size is sufficient for them to invade tumor spheroids and destroy them from within,” Dokholyan noted.
The team tested the modified NK cells against two types of solid tumor spheroids, one derived from human breast cancer cells and the other from human cervical cancer cells. The engineered cells effectively killed the tumor cells within seven days. In comparison, unmodified NK cells could only attack the tumors from the outside and could not penetrate, leading to continued tumor growth. They also tested re-engineered immune cells from mice against tumor spheroids created from mouse melanoma cells.
While the initial results are promising, Dokholyan stressed that this research is still in its early phases and further investigations are needed to assess the technology for potential clinical applications. He also hopes to investigate additional activation stimuli that could adjust protein functions and influence cellular behavior.
Other contributors from Penn State included Todd Schell, professor of microbiology and immunology; Brianna Hnath, a doctoral candidate in biomedical engineering; Congzhou Mike Sha, a joint degree student in the MD/PhD Medical Scientist Training Program; and Lynne Beidler, a research technologist. First author Jiaxing Chen was a doctoral student during the research and is now a postdoctoral researcher at the University of Pennsylvania.
This research received funding from the National Institutes of Health and the Passan Foundation.
