The groundbreaking success of mRNA vaccines against SARS-CoV-2 during the COVID-19 pandemic has revolutionized vaccine science. Today, this Nobel Prize-winning technology is being repurposed in the battle against cancer, with experimental mRNA vaccines currently undergoing trials for melanoma, small cell lung cancer, bladder cancer, and various other malignancies. Researchers are optimistic that these innovative vaccines could ultimately lead to powerful new strategies for cancer prevention and treatment.
A recent study from Washington University School of Medicine in St. Louis unveils a surprising aspect of how these cancer vaccines function. Experiments conducted on mice have shown that mRNA cancer vaccines maintain high efficacy even in the absence of immune cells traditionally deemed essential. Instead, other closely related immune cells stepped in to launch a robust assault against the tumor.
The findings, published in Nature, offer fresh insights into the immune system’s response to mRNA vaccines and could aid researchers in designing more effective cancer immunizations in the future.
“There is a significant interest in leveraging the mRNA vaccine technology used during the COVID-19 pandemic to foster antitumor immunity,” stated 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 their responses provides vaccine developers with vital mechanistic insights to enhance tumor-targeting vaccines.”
Murphy is also a research member of the Siteman Cancer Center, affiliated with Barnes-Jewish Hospital and WashU Medicine.
How mRNA Cancer Vaccines Activate the Immune System
mRNA vaccines deliver genetic blueprints known as messenger RNA (mRNA) that instruct immune cells to generate small protein fragments. These protein pieces train the immune system to identify and attack cells expressing the same proteins. For cancer vaccines, these proteins are specifically chosen because they are unique to tumors, enabling immune cells to recognize and eliminate cancer cells while sparing healthy tissue.
Central to this process is a group of immune cells called dendritic cells, which produce protein fragments based on mRNA instructions. Another type of immune cell, known as T cells, seeks out and destroys the cells that harbor these proteins.
Previous beliefs held that a specific dendritic cell subtype, cDC1, was primarily responsible for initiating this immune response. Although cDC1s are renowned for activating T cells against virus-infected cells, scientists had limited understanding of whether this mechanism also applies after mRNA vaccination against viruses or cancer.
For this study, Murphy teamed up with co-author William E. Gillanders, MD, the Mary Culver Professor of Surgery at the University of Washington School of Medicine. The research team utilized mouse models that were deficient in either cDC1 cells or a related subtype, cDC2, to investigate how each cell type contributes to the immune response following mRNA cancer vaccination.
Gillanders, a physician-scientist and surgical oncologist, is 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 outcome. Mice vaccinated with the mRNA cancer vaccine still mounted strong T cell responses, even in the absence of cDC1 cells.
These mice were also able to eliminate sarcoma tumors, a type of cancer that arises in connective tissues like fat, muscle, nerves, blood vessels, bone, and cartilage. The successful tumor eradication, despite the lack of cDC1 cells, led researchers to conclude that cDC2 cells must play a role in activating the cancer-fighting response.
The study highlighted cDC2 cells’ ability to activate T cells and inhibit tumor growth. Interestingly, T cells activated through cDC1 and cDC2 exhibited distinct molecular “fingerprints,” indicating that they may serve complementary functions. These variations may offer researchers new avenues for enhancing future cancer vaccines.
The research team also discovered that vaccinated mice lacking cDC2 cells, as well as those with both dendritic cell subtypes present, successfully launched an immune response to reject tumor growth. Collectively, these findings demonstrate that mRNA cancer vaccines depend on both cDC1 and cDC2 cells to elicit effective antitumor immunity.
Newly Identified Vaccine Mechanism
Further experiments indicated that cDC2 cells activate T cells in an indirect manner. Instead of producing the vaccine protein directly, they rely on neighboring cells to read the mRNA instructions, create the protein, fragment it, and display those segments on their surfaces.
These cells transfer membrane complexes carrying protein fragments to cDC2 cells through a process known as “cross-dressing.” The cDC2 cells subsequently present tumor proteins to T cells, initiating an immune attack.
“This study uncovers a new mechanism through which mRNA vaccines engage the immune system via both cDC1 and cDC2 cells. This enhances our understanding of their potency and offers researchers tangible targets for improving future mRNA cancer vaccines,” explained Gillanders. “It could optimize vaccine formulations and dosing, clarify why some patients have better responses to vaccines than others, and inform strategies to enhance vaccine efficacy.”
Source: www.sciencedaily.com