The emergence of SARS-CoV-2 mRNA vaccines in 2020 changed the course of the COVID-19 pandemic. Now, the Nobel Prize-winning technology is being adapted to fight cancer, with mRNA vaccines in clinical trials for melanoma, small cell lung cancer and bladder cancer, among others, opening the door to new ways to prevent and treat the disease.
The scientists hypothesized that a specific subtype of immune cells is required for mRNA vaccination to activate the immune system. But researchers at Washington University School of Medicine in St. Louis show in a new study in mice that even without these cells, the mRNA vaccine still elicits strong cancer-killing responses. That’s because, they discovered, a cousin of this immune cell subtype can also stimulate antitumor immune activity—an unexpected finding given that this related subtype is not involved in responses to other vaccines.
The findings are published April 15 in Natureoffering a deeper understanding of how the immune system responds to mRNA vaccination and guiding the optimal design of a cancer vaccine.
There is great interest in applying the mRNA vaccine approaches used during the COVID-19 pandemic to the problem of inducing anti-tumor immunity. By analyzing which immune cells are involved and how they coordinate the response, we offer vaccine developers some additional mechanistic insights to consider in their goal to optimize these anti-tumor protein vaccines.”
Kenneth M. Murphy, MD, PhD, senior author, the Eugene Opie Centennial Professor of Pathology & Immunology at WashU Medicine
Murphy is also a research fellow at the Siteman Cancer Center, based at Barnes-Jewish Hospital, and at WashU Medicine.
Unconventional immune pathway
mRNA vaccines work by providing instructions, in the form of messenger RNA biomolecules, for immune cells to produce pieces of protein that trigger the immune system to destroy cells that carry those proteins. So-called dendritic cells produce the protein pieces from the mRNA instructions, and T cells – another immune cell – are the ones that seek out and destroy. mRNA vaccines can be designed to create pieces of protein unique to a tumor so that T cells eliminate those cancer cells.
cDC1, a classical type 1 dendritic cell, has long been known to be an effective tutor, priming T cells to attack cells infected by a virus. But less is known about how T cells are activated after an mRNA vaccine, either against a virus or a tumor. Working with study co-author William E. Gillanders, MD, the Mary Culver Professor of Surgery at WashU Medicine, Murphy and members of his lab used mouse models lacking cDC1 or a related cell subtype known as cDC2 to determine the role played by different groups of mccnation TRNA cancer cells.
Gillanders, a physician-scientist and surgical oncologist who has also developed an investigational vaccine against triple-negative breast cancer, treats patients at the Siteman Cancer Center.
As part of the research, the scientists discovered that mice immunized with an mRNA vaccine generated strong T-cell responses even in the absence of cDC1. In addition, they found that immunized mice lacking cDC1 were able to clear sarcoma tumors – cancers that develop in connective tissues such as fat, muscle, nerves, blood vessels, bone and cartilage. This indicated that some other cell type must stimulate the T-cell response.
Indeed, their study found that cDC2s are also involved in generating an immune response from T cells and preventing tumor growth. The study also found that T cells activated by cDC1 and cDC2 displayed slightly different molecular ‘fingerprints’. These differences could help scientists design better versions of vaccines in the future.
Similarly, immunized mice lacking cDC2 and mice that had both cell subtypes produced an immune response and rejected tumor growth, demonstrating that mRNA vaccination uses both dendritic cell subtypes to stop cancer.
Further investigation of cDC2s suggested that they activate T cells through an outsourcing process that relies on other cells to use mRNA instructions to make the protein, cleave it, and present small fragments on its surface. Once the protein is processed and presented, these cells then transfer the membrane complex that holds the fragment in place on the cell surface to cDC2 to engage with T cells – through a process already known as “cross-ligation”.
“This work reveals a new way mRNA vaccines engage the immune system—via cDC1 and cDC2—that explains their potency and gives researchers specific targets to make future mRNA cancer vaccines more effective,” Gillanders said. “It could improve vaccine formulation and dosing, potentially explain why some patients respond better to vaccines than others, and guide strategies to make vaccines more effective.”
