How mRNA cancer vaccines still destroy tumors when a key immune cell is missing
By Marta Wegorzewska, Washington University in St. Louis
Edited by Lisa Lock, reviewed
by Andrew Zinin
The advent of mRNA vaccines against SARS-CoV-2 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 of preventing and treating the disease.
Scientists assumed that one specific immune cell subtype was
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 triggers strong
cancer-killing responses. That's because, they found, a cousin to this subtype
of immune cell can also stimulate anti-tumor immune activity—an unexpected
finding given that this related subtype is not involved in responses to other
vaccines.
The findings are published in Nature,
offering a deeper understanding of how the immune system responds to mRNA
vaccination and guiding the optimal design of a cancer vaccine.
"There is a lot of interest in applying the mRNA vaccine approaches used during the COVID-19 pandemic to the problem of inducing anti-tumor immunity," said senior author Kenneth M. Murphy, MD, Ph.D., the Eugene Opie Centennial Professor of Pathology & Immunology at WashU Medicine. "By dissecting which immune cells are involved and how they coordinate the response, we're offering vaccine developers some additional mechanistic insights to consider in their goal of optimizing these vaccines against tumor proteins."
Murphy also is a research member at Siteman Cancer Center,
based at Barnes-Jewish Hospital and WashU Medicine.
mRNA vaccines work by delivering instructions, in the form
of messenger RNA biomolecules, for immune cells to produce bits of protein that
trigger the immune system to destroy cells bearing these proteins. So-called
dendritic cells produce the protein bits from the mRNA instructions, and T
cells—another immune cell—are the ones that seek and destroy. mRNA vaccines can
be designed to generate protein bits unique to a tumor so that T cells
eliminate those cancerous cells.
cDC1, a classical type 1 dendritic cell, has long been known
to be an effective teacher, priming T cells to attack cells infected by a
virus. But less is known about how T cells become activated after an mRNA
vaccine, whether against a virus or a tumor. In collaboration with the study's
co-corresponding author William E. Gillanders, MD, the Mary Culver Professor of
Surgery at WashU Medicine, Murphy and members of his lab used mouse models that
lacked cDC1 or a related cell subtype known as cDC2 to tease out the role that
different groups of dendritic cells play in priming T cells after mRNA cancer
vaccination.
Gillanders, a physician-scientist and surgical oncologist
who also has developed an investigational
vaccine against triple-negative breast cancer, treats patients at
Siteman Cancer Center.
As part of the research, the scientists found that mice
immunized with an mRNA vaccine generated strong T-cell responses even in the
absence of cDC1s. In addition, they found that immunized mice without cDC1s
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 be stimulating the T-cell response.
Indeed, their study found that cDC2s also
participate in generating an immune response from T cells and preventing tumor
growth. The study also found that T
cells turned on by cDC1s and cDC2s each showed slightly different
molecular "fingerprints." These differences could help scientists
design better versions of vaccines in the future.
Similarly, immunized mice lacking cDC2s 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 they activate T
cells through an outsourcing process that relies on other cells to use the mRNA
instructions to make the protein, chop it up and present small fragments on its
surface. Once the protein is processed and presented, those cells then transfer
the membrane
complex that holds the fragment in place on the cell's surface to the
cDC2 to engage with the T cells—through an already-known process referred to as
"cross dressing."
"This work uncovers a new way mRNA vaccines engage the
immune system—through both cDC1 and cDC2—which helps explain their power and
gives researchers concrete targets for making future mRNA cancer vaccines more
effective," said Gillanders. "It could improve vaccine formulation
and dosing, potentially explain why some patients respond better to vaccines
than others and guide strategies for making vaccines more effective."
Publication details
Suin Jo et al, mRNA vaccines engage unconventional pathways
in CD8+ T cell priming, Nature (2026). DOI:
10.1038/s41586-026-10353-6