mRNA vaccines, best known for their role in combating COVID-19, work by delivering genetic instructions that enable cells to produce a target protein, which in turn triggers an immune response. When the mRNA is injected into the body, both immune and non-immune cells can take up and express the mRNA. For years, researchers have assumed that getting the mRNA into dendritic cells—the immune cells that activate T cells—was essential.
However, a new study from Mount Sinai shows that is not the case. While dendritic cells are still important, mRNA delivery to them is not required to trigger an immune response. These findings provide a new framework for designing mRNA vaccines and mRNA therapeutics.
Immune cells and responses
In the new study, published in Nature Biotechnology, the researchers employed a technology to precisely control where mRNA is expressed in the body. By incorporating microRNA target sites into the mRNA, they were able to selectively “turn off” mRNA expression in specific cell types—including dendritic cells, hepatocytes (liver cells), and muscle cells.
Using the microRNA target sites, the team made a surprising discovery: mRNA expression in dendritic cells and other immune cells is not required to generate strong T cell responses, including against SARS-CoV-2 antigens.
“This was unexpected. It tells us that other cells are producing the vaccine antigen and handing it off to the immune system. That process, called cross-presentation, was known to be key for traditional vaccines. We now know it is also important for mRNA vaccines, and this changes how we think about their design,” said senior author Brian Brown, Director of the Icahn Genomics Institute at the Icahn School of Medicine at Mount Sinai. Brown also developed the technique to control where mRNA is expressed in the body.
More effective cancer vaccines
Critically, the study showed especially strong cancer vaccine responses. In mice with lymphoma, an mRNA vaccine engineered to avoid hepatocyte expression led to an over 50% reduction in tumor burden. This was because the hepatocyte-silenced vaccine boosted more killer T cells than the traditional mRNA vaccine.
“These results show that we can make mRNA cancer vaccines more effective simply by controlling where the mRNA-encoded antigen is expressed,” says cancer vaccine expert Josh Brody, MD, Director of the Lymphoma Immunotherapy Program at the Mount Sinai Tisch Cancer Center and one of the study authors. “It’s a new lever for improving immunotherapy.”
The study also found that silencing the mRNA in hepatocytes reduced hepatocyte death when the mRNA was used to boost pre-existing T cells, an important finding for therapies involving gene editing or CAR-T cells.
mRNA vaccine immunity
Another surprising finding from the study was the role of different non-immune cell types in mRNA vaccination. The researchers found that when mRNA expression was turned off in muscle fibers, the T cell response was reduced. In contrast, when mRNA expression in hepatocytes was turned off, the T cell response was tripled. This demonstrates that these non-immune cells contribute to mRNA vaccine immunity—which was not previously known.
While the study was conducted in animal models, the researchers note that the underlying immune mechanisms are conserved and likely to translate to humans. Next, they plan to harness the technology to further improve mRNA treatments for solid organ cancers and create mRNA vaccines that can be used to treat autoimmune diseases.