Cancer immunotherapy, a type of treatment that recruits our own immune cells to attack tumors, has revolutionized the way many types of cancer are treated. One type of immunotherapy being investigated uses natural killer cells, a type of immune cell that can seek out and destroy harmful cells. However, current strategies to stimulate these cells to take advantage of their tumor-killing capabilities are expensive and time-consuming. To overcome this, NIBIB-funded researchers are developing a method to activate natural killer cells using an external magnetic field, which not only enhances their cytotoxicity but allows them to be tracked using magnetic resonance imaging (MRI) to verify that they have reached their target.
“Adoptive cell therapies, in which immune cells are removed from the body, modified to better attack cancer cells, and infused back into the patient, represent a major advance in cancer treatments,” said Tatjana Atanasijevic, Ph.D., director of the NIBIB program in Molecular Probes and Imaging Agents. “This first work describes a new and creative way to stimulate natural killer cells by modifying them with magnetic nanocomplexes, facilitating their activation upon exposure to a magnetic field and enabling an image-guided treatment approach.”
How do natural killer cells work? These white blood cells are part of the innate immune response, meaning they can kill harmful cells (such as cancer cells or infected cells) without having been previously exposed to them. They do this by looking for specific receptors on neighboring cells that identify them as “self,” meaning they belong to the body. If the cell does not have these receptors, the natural killer cell considers it “foreign” and releases a cocktail of cytotoxic molecules that penetrate the aggressor cell and cause its death.
While natural killer cells are efficient and lethal, cancer cells can find ways to evade them, especially in established tumors. One strategy to “boost” natural killer cells is to incubate them with specific substances. interleukinsor signaling molecules that stimulate natural killer cells and enhance their lethality (or cytotoxicity). However, this process is time-consuming and expensive, and this approach has resulted in limited clinical success, especially in solid tumors.
In addition to signaling molecules, natural killer cells can be stimulated by physical interactions with their environment, such as traveling through the bloodstream, passing through tight spaces, or attaching to other cells. These physical interactions can exert force on natural killer cells and activate them, a concept known as mechanical force-mediated immune signaling. “Instead of priming natural killer cells with interleukins, we are investigating an alternative way to stimulate these cells by subjecting them to mechanical forces,” explained Dong-Hyun Kim, Ph.D., associate professor at Northwestern University.
But their strategy does not rely on typical environmental interactions to exert these mechanical forces. Rather, Kim and his colleagues are attaching magnetic nanocomplexes to natural killer cells and then subjecting them to a magnetic field.
“The magnetic field can remotely control the movement of the nanocomplexes, which in turn applies a mechanical force to the natural killer cells to which they are attached,” Kim said. These perturbations caused by the magnetic field “pull” on parts of the cell, telling them to generate cytotoxic molecules, he explained. “By applying appropriate magnetic field conditions, we can cause natural killer cells to generate and secrete molecules that enhance their cytotoxicity and tumor-killing potential.”
In their study, reported in ACS NanoThe team evaluated their magnetoactivated natural killer cells both in a culture dish with human liver cancer cells and in a rat liver cancer model. They found that magnetoactivated natural killer cells had significantly higher cytotoxicity compared to unmodified natural killer cells in their cell culture experiments. Furthermore, in animal experiments, treatment with magnetoactivated natural killer cells resulted in a reduced tumor growth rate compared to treatment with modified natural killer cells that were not stimulated by an external magnetic field.
Another advantage of magnetized natural killer cells is their ability to be monitored in the body using MRI. “MRI visibility of our labeled natural killer cells allows us to confirm their successful arrival to the tumor region,” Kim said. In fact, using MRI, the researchers were able to guide the release of their magnetized natural killer cells and verify that they had reached liver tumors in their animal studies.
Kim highlighted the preclinical nature of this feasibility study and noted that more rigorous research is needed before this method can be translated to humans.
This study was supported by a grant from the NIBIB (EB026207) and a grant from the National Cancer Institute (NCI; CA218659).
Study reference: Taehoon Sim, Bongseo Choi, Soon Woo Kwon, Kwang-Soo Kim, Hyunjun Choi, Alexander Ross and Dong-Hyun Kim. Magnetoactivation and magnetic resonance imaging of natural killer cells labeled with magnetic nanocomplexes for the treatment of solid tumors. ACS Nano 2021 15 (8), 12780-12793. DOI: 10.1021/acsnano.1c01889
This Science Highlight describes a basic research finding. Basic research increases our understanding of human behavior and biology, which is critical to promoting new and better ways to prevent, diagnose, and treat diseases. Science is an unpredictable and incremental process: each research advance builds on past discoveries, often in unexpected ways. Most clinical advances would not be possible without knowledge of fundamental basic research.
