According to a study published by Pritzker School of Molecular Engineering professors Nicholas Chevrier and Surya Pandey—along with Pritzker software engineer Adam Gruenbaum, Max Delbrück Center scientists Tamara Kanashova and Philipp Mertins, and Harvard physicist Philippe Cluzel—human immune cells have an identifiable system by which they react to foreign invaders in the body, depending on the structure of the invading organism.
The November 2020 study, titled “Pairwise Stimulations of Pathogen-Sensing Pathways Predict Immune Responses to Multi-adjuvant Combinations,” includes among its results “a general property for the combinatorial sensing of microbial signals.” In other words, the study explored the process by which immune cells react to disease-causing agents in the body. The study also identified immune cell therapy as a potential treatment for melanoma via testing on mice.
To further understand this scientific development, The Maroon spoke with Pandey, an author of the paper and a staff scientist in the Chevrier lab.
One of the human immune system’s primary purposes is to protect us from pathogens, which are microorganisms that can cause disease. The ways by which our immune system can best combat pathogens are still not completely understood. Pandey noted that the complexity of immune responses to pathogens made research on the subject difficult.
“Our immune cells have different kinds of receptors to sense one kind of molecular entity in one specific way, and that’s how they mount the immune response,” Pandey said. “But when a pathogen comes, it is a composite of all these different things and it activates different kinds of signaling receptor pathways.” Because pathogens trigger complex, multi-step responses in immune cells, it has been difficult for past scientists to patch together the entire process by which immune cells respond to different pathogens.
Pandey also explained that, prior to their paper, there had been a lack of research concerning immune cell responses involving signaling pathways, a term that refers to methods by which the immune system initiates a response after sensing a pathogen.
“All signaling receptor pathways have been studied one pathway at a time,” Pandey said. “People knocked out one molecule of a pathway and then studied what happens. There have been no systematic studies for what happens when all these signaling pathways get activated.”
Knowing this, the researchers decided to take dendritic cells with antigens bound to them and expose them to different combinations of ligands—substances bound to molecules in organisms for specific purposes—in single, pairs, and triplets in order to see how these pathways would react. This study would help the team understand the effects of different combinations of these molecules on the immune system.
Researchers found that in testing single, pairs of, and triplets of ligands, the effects of the triplets could be predicated based on the single and pairwise results, therefore meaning that triplets did not result in a significantly different response compared to single and pair combinations of ligands. The finding indicates that the immune response of the human body, while complex, is not as complicated as once thought.
The second part of the experiments involved applying this newfound knowledge directly to cancer research. “We took advantage of melanoma tumor models in mice, and we made our dendritic cell vaccines,” Pandey said. They injected dendritic cell vaccines of 200 different ligand combinations into mice that had already been injected with B16 melanoma cells. Out of the initial 200, four combinations proved capable of significantly reducing tumors with a single dose.
In conclusion, the team found that pairwise stimulations were the key factor in determining which ligands were able to most effectively stir immune cells into action. They determined that utilizing multiple signaling pathways to trigger specific immune responses at once is possible. In essence, immune responses are now easier to track depending on the pathogen, and that makes it easier for scientists to develop drugs to counter those pathogens.
