The body is equipped with a robust defense system that vigilantly protects us from tiny threats like infections and cancer. At the forefront of this defense is the macrophage, a type of white blood cell that patrols tissues, consuming pathogens, debris, dead cells, and cancerous cells. Macrophages have a challenging role; they must be careful to overlook healthy cells during their patrol to avoid initiating an autoimmune response.
The body is equipped with a robust defense system that vigilantly protects us from tiny threats like infections and cancer. At the forefront of this defense is the macrophage, a type of white blood cell that patrols tissues, consuming pathogens, debris, dead cells, and cancerous cells. Macrophages have a challenging role; they must be careful to overlook healthy cells during their patrol to avoid initiating an autoimmune response.
Researchers at UC Santa Barbara aimed to uncover how these immune cells decide what to consume and when. A study published in Developmental Cell details how the team programmed macrophages to respond to light to study how their interactions with cancer cells influence their appetite. Senior author Meghan Morrissey, an assistant professor in the Department of Molecular, Cellular, and Developmental Biology, noted, “We found that giving macrophages an appetizer makes them hungrier for their next meal.”
The findings provide a new approach to enhance the effectiveness of cancer immunotherapies that utilize macrophages to fight the disease. They also present a more intricate overview of trained immunity, a type of memory seen in the innate immune system that researchers have recently started to recognize.
Using light to control cell appetite
While observing the body, macrophages seek out cells and debris labeled with the IgG antibody by other immune cells. These antibodies serve as “eat me” signals, which macrophages recognize through Fc receptors (FcR) present in their cell membrane. Once activated by IgG, these receptors cluster together, and after reaching a certain threshold, the macrophage engulfs the target.
Lead author Annalise Bond, a doctoral student in Morrissey’s lab, devised another method to cluster the FcR without IgG’s involvement. Collaborating with UCSB professor Max Willson, she designed a synthetic protein that merges parts of the FcR receptor with cryptochrome 2 (CRY2). This protein clusters when activated by blue light, allowing Bond to control the system precisely and activate the FcR at her discretion.
The approach was a success. Bond utilized light to encourage macrophages to ingest silica beads coated with a lipid membrane to simulate cancer cells, all without the need for IgG. This allowed them to provide the macrophages with a “light snack” to observe its impact on their future eating patterns.
Pavlov’s macrophages
Bond stimulated the engineered macrophages with light and then had them wait for varied periods. Afterward, she offered them the mock cancer cells presenting the IgG “eat me” antibody.
The group activated with light ate significantly more after their simulated snack than the control group, which did not possess light-activated FcR. “I’ve likened it to Hungry Hungry Hippos,” Bond explained, “because they just devour everything in sight.” Moreover, stimulating the FcR with subthreshold amounts of the IgG antibody on cancer cells readied the macrophages for their next meal.
However, excessive stimulation negated this effect. “If macrophages received so much IgG that they actually consumed, it was akin to a meal, not an appetizer. They weren’t hungry anymore,” Morrissey clarified.
While the authors aren’t entirely sure why macrophages exhibit this behavior, they have a theory. When scouting healthy tissue, macrophages prioritize preventing autoimmunity, establishing a high activation threshold. However, upon noticing indications of an issue via IgG antibodies, their focus shifts to removing the infection, willing to risk some tissue damage if necessary, according to Morrissey.
What’s happening inside?
The macrophages’ appetite spikes about an hour after the initial stimulation before decreasing and then rising again after four hours. Bond was intrigued by what underpinned this pattern. “One hour is far too quick for the cell to synthesize new proteins,” Morrissey remarked, indicating that a different mechanism must be at play.
Indeed, even when Bond inhibited protein synthesis, the macrophages maintained their short-term priming, suggesting alternative controls for this response. However, blocking protein synthesis eliminated the enhanced long-term appetite, showing that this behavior relies on alterations in gene expression and protein synthesis.
Through further research, Bond determined that subthreshold activation of FcR spurred changes in the receptors’ movement across the cell membrane. This activity increases the receptors’ mobility, facilitating their aggregation more efficiently under IgG exposure within roughly an hour. Concurrently, the cell begins to upregulate specific genes and produce new proteins, explaining the longer-lasting effects.
“This short-term mechanism is particularly intriguing because it represents a different variety of immune memory than previously observed,” Morrissey commented.
Hungry macrophages tackle more cancer
Macrophages find antibodies like IgG hard to resist, consuming nearly anything marked with them, including the glass beads used in Bond’s research. As a result, monoclonal antibodies have become a widely used treatment for various conditions, including many cancer therapies. Bond successfully enhanced the efficacy of a common antibody (Rituximab) utilized for lymphoma treatment.
The findings by Bond and Morrissey imply that multiple smaller doses of antibody therapy may be more beneficial than a single large one, as earlier doses prepare the cells for the subsequent treatment. Oncologists have observed this through practical experience.
Additionally, other macrophage-based therapies might gain from pretreatment—such as exposing engineered macrophages to IgG before introducing them to the patient, effectively priming them to engulf more cancer cells.
A spectrum of memory
Historically, biologists and physicians believed only the adaptive segment of the immune system possessed any form of immunological memory; however, a more nuanced perspective is emerging.
This research demonstrated that even components of the immune system not typically associated with memory can react to stimuli, indicating that immunological memory exists on a spectrum. Some cells respond to immediate threats; others can remember infections for years, while macrophages exhibit characteristics that place them somewhere in between.
The study also offers a more intricate view of macrophages, suggesting that they are more complex decision-makers than previously understood. “Macrophages must assess their surroundings,” Morrissey noted. “Are they in healthy tissue and need to avoid autoimmunity, or are they combating an infection and need to act decisively?”
Exploring further intricacies
Macrophages possess two types of Fc receptors: one that boosts their appetite and another that suppresses it, both activated by IgG. Macrophages generally have a higher count of activating receptors, which ultimately prevail. However, the rationale for having both types instead of a straightforward abundance of activating FcR remains unclear.
This is a puzzle that Bond is keen to solve. “Now that I have this toolkit to investigate macrophage appetite, I’m eager to understand the role of the inhibitory FcR,” she said. The technique she has developed allows her to isolate the activation of a single FcR, potentially enabling her to uncover the inhibitory FcR’s contribution in her forthcoming studies.
