The success of mRNA vaccines against SARS-CoV-2 during the COVID-19 pandemic has transformed vaccine science. Today, the same Nobel Prize-winning technology is being applied in the fight against cancer, with experimental mRNA vaccines already being tested against melanoma, small cell lung cancer, bladder cancer, and several other cancers. Researchers hope that these vaccines could eventually provide powerful new ways to prevent and treat the disease.
A new study from Washington University School of Medicine in St. Louis reveals an unexpected feature of how these cancer vaccines work. Scientists have discovered in experiments on mice that mRNA cancer vaccines remain highly effective even when immune cells long considered essential are missing. Instead, other closely related immune cells stepped in and mounted a powerful attack against the tumor.
The survey results are natureprovides new insights into how the immune system responds to mRNA vaccines and could help researchers design more effective cancer vaccines in the future.
“There is a lot of interest in applying the mRNA vaccine approach used during the COVID-19 pandemic to the problem of inducing antitumor immunity,” said lead author Kenneth M. Murphy, MD, Eugene Opie Centennial Professor of Pathology and Immunology at WashU Medicine. “Analyzing which immune cells are involved and how they coordinate responses provides vaccine developers with additional mechanistic insights to consider in their goal of optimizing vaccines against tumor proteins.”
Murphy is also a research member of the Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine.
How mRNA cancer vaccines activate the immune system
mRNA vaccines carry genetic instructions known as messenger RNA that instruct immune cells to produce small pieces of protein. These protein fragments train the immune system to recognize and attack cells that carry the same protein. For cancer vaccines, these proteins are chosen because they are specific to tumors and allow immune cells to identify and destroy cancer cells, with little effect on healthy tissue.
A group of immune cells called dendritic cells play a central role in this process by producing protein fragments from mRNA instructions. Another type of immune cell known as a T cell seeks out and destroys cells carrying these proteins.
Researchers have long believed that one dendritic cell subtype called cDC1 is primarily responsible for this response. Although cDC1s are well known for priming T cells to attack virus-infected cells, scientists did not fully understand whether the same process occurs after mRNA vaccination against viruses or cancer.
For the study, Murphy collaborated with co-author William E. Gillanders, MD, the Mary Culver Professor of Surgery at the University of Washington School of Medicine. The research team used mouse models lacking either cDC1 cells or a related subtype called cDC2 to investigate how each cell population contributes to the immune response after mRNA cancer vaccination.
Gillanders, a physician-scientist and surgical oncologist, is also developing an investigational vaccine for triple-negative breast cancer and treats patients at the Siteman Cancer Center.
Unexpected immune cell intervention
The experiment revealed an unexpected result. Mice vaccinated with the mRNA cancer vaccine still generated strong T cell responses even when lacking cDC1 cells.
These same mice were also able to remove sarcoma tumors, which are cancers that develop in connective tissue such as fat, muscle, nerves, blood vessels, bone, and cartilage. Because the tumor was successfully eliminated despite the absence of cDC1 cells, the researchers concluded that another type of immune cell must be contributing to activating the cancer-fighting response.
Their study pointed to cDC2 cells.
This study showed that cDC2 cells can also activate T cells and prevent tumor growth. Interestingly, T cells activated by cDC1 and cDC2 each exhibit slightly different molecular “fingerprints,” suggesting that they may play complementary roles. These differences may provide researchers with new opportunities to improve future cancer vaccines.
The research team also found that vaccinated mice lacking cDC2 cells, as well as mice with both dendritic cell subtypes intact, successfully mounted an immune response and rejected tumor growth. Collectively, these findings demonstrate that mRNA cancer vaccines rely on both cDC1 and cDC2 cells to generate effective antitumor immunity.
Newly identified vaccine mechanism
Further experiments revealed that cDC2 cells appear to activate T cells through an indirect process. Rather than producing the vaccine protein itself, it relies on other cells to read the instructions in the mRNA, manufacture the protein, break it into smaller pieces, and display those pieces on its surface.
These cells then transfer membrane complexes carrying protein fragments to cDC2 cells through a known process called “cross-dressing.” The cDC2 cells then present tumor proteins to T cells, which help mount an immune attack.
“This study reveals a new way in which mRNA vaccines engage the immune system through both cDC1 and cDC2. This helps explain their power and provides researchers with concrete targets to make future mRNA cancer vaccines more effective,” said Gillanders. “It could improve vaccine formulation and dosing, explain why some patients respond better to vaccines than others, and guide strategies to make vaccines more effective.”
