The body’s immune system defeats diseases by sensing foreign invaders, such as bacteria or viruses, and then responding to them.
But just how immune cell receptors work together to sense more molecules and make these decisions remains a mystery. Now, researchers at the Pritzker School of Molecular Engineering (PME) at the University of Chicago have discovered a general ability to understand how these cells sense and respond to microbial signals.
Studying how molecules affect immune cells, they found that although the effect of one molecule does not predict the effect of two molecules together, the complexity stops there. In fact, the effect of singles and pairs of molecules can be used to predict how triple molecules work.
The result, led by ast. Prof. Nicola Chevrier published it on October 27 in the magazine Mobile systems, lead to more effective immunotherapy against cancer in mice and may lead to more effective vaccines for both existing and new viruses.
The key to designing vaccines
Each of the body’s innate immune cells has receptors that recognize molecules from foreign pathogens. To fight bacteria or viruses, these cells make decisions in response to complex combinations of inputs from those molecules. Although researchers have studied single paths, how these paths work together is still not well understood.
Chevrier and his colleagues sought to better understand how cells integrate multiple signals into a response. Not only would it help answer the basic fundamental question of biology, but also design vaccines that use adjuvants, molecules that help modulate the immune system and increase its response.
Although only a few vaccines are currently used, adjuvants may be the key to developing new types of vaccines. Currently, FDA-approved supplements target only one or two receptors on a cell. If researchers could find the right combination to target more, vaccines could become more effective.
Understand how combinations work together
Chevrier and co-workers used adjuvants to stimulate immune cells in petri dishes to understand what happens when single molecules, pairs of molecules and triple molecules are used. If the results were additives, the effects of one molecule and the effects of another molecule, when combined, would remain the same. The researchers found that this was not the case – two molecules combined together had different effects than each had individually.
But they found that the effect of single molecules and pairs of molecules could accurately predict what happened to triple molecules.
“It could have been infinitely complex, but it is not,” Chevrier said. “We are the first to show that you can predict higher order effects across immune pathways with very simple models.”
A model used to design immunotherapy for cancer
To prove their theory, the researchers injected cells conditioned with certain combinations of adjuvants – creating a specific immunotherapy treatment for cancer – into a mouse model of tumors. The answer was potent: tumors grew five to ten times less often in treated mice than in untreated mice.
That was very encouraging. “Now we need to better understand the mechanisms why this worked so well.”
Chevrier, University of Chicago
Researchers also hope to find new combinations of adjuvants that have equally powerful effects and eventually conduct a clinical trial in humans.
“Now that we can predict the effects of multiple adjuvants with little data and a simple model, we need to extend this knowledge to designing vaccines against both new and old threats,” Chevrier said.
Pandi, S., etc. (2020) Stimulation in pairs of pathogen-sensitive pathways predict immune responses to multi-adjuvant combinations. Mobile systems. doi.org/10.1016/j.cels.2020.10.001.