Immune cells keep our bodies safe and healthy from foreign pathogens. Each is responsible for various functions, but a common trait among these cells is the ability to recognize and eliminate infections or disease. Prominent immune cells with increased lytic activity include macrophages, neutrophils, and T cells. All three have been reported to target infected cells, specifically macrophages. Macrophages in tandem with other cells survey tissues looking for particles, debris, and other deleterious cells or proteins to consume and clear from the body. Interestingly, these cells are extremely efficient and do not target healthy cells.
Scientists are studying how to harness macrophages to improve their function as well as direct them toward infected cells that are able to escape immune barriers and continue to proliferate. A recent report in Developmental Cell, by Dr. Meghan Morrissey and others, demonstrate that macrophages can be primed to improve their antitumor activity and effectively eliminate cancer cells. Morrissey is an Assistant Professor in the Department of Molecular, Cellular, and Developmental Biology at University of California, Santa Barbara (UCSB). She studies how macrophages consume and digest foreign particles at the site of injury or infection. More specifically, her lab tries to understand the inter- and intracellular signaling that generate a response from macrophages.
Morrissey and her team found that giving macrophages a small piece of debris to consume increases their lytic function. This finding has major implications for the enhancement of immunotherapies that work to improve the antitumor function of immune cells. Additionally, it indicates that the immune system can be trained and exhibit memory for pathogens that repeatedly enter the body. However, for macrophages to consume infected cells, they must activate after a specific threshold is reached triggered by a compounding of signals from surface receptors. These surface receptors that generate enough signal to activate macrophages are known as Fc receptors (FcR). Morrissey and her team were able to synthetically develop a system to activate macrophages using blue light, which provided control over the macrophage and what it targets. Interestingly, researchers were able to prime macrophages by directing them to target small amounts of debris or cells to then improve their lytic function against tumors.
Morrissey and her team engineered the macrophages to respond to blue light and found they do a great job at targeting cancer cells. However, if the macrophages were overly stimulated, then their antitumor activity would disappear. Researchers describe this process like eating a meal. If the macrophages are primed with the consumption of a small number of debris or cells, it is like an appetizer, and are still ‘hungry’ for more. Alternatively, if they ‘eat’ too much prior, their ability to consume cancer cells diminishes. Investigating the mechanism behind this, researchers found that gene expression is changing at the same time as the movement of surface receptors that generate activity. This discovery sheds light on the process by which macrophages consume other cells.
Morrissey and her team used their engineered macrophages to improve other therapies used to treat lymphoma. They discovered that small doses given to macrophages improves their antitumor activity which sensitizes the cancer cells to other therapies. Based on this research, scientists believe they could also pre-treat macrophages before administering them to a patient to enhance therapeutic efficacy. While this work demonstrates incredible promise for patients in the clinic, it is important to thoroughly understand the mechanism of this process. Morrissey and her team hope to continue their investigation and further enhance cell consumption efficiency of macrophages to better treat cancer and improve patient care.