Investigators from Mass General Brigham have developed a way to promote antitumor immunity by hijacking cellular machinery within cancer cells. The study demonstrated that inducing cancer cells to produce an immune-activating molecule led to reduced tumor growth in preclinical models. Results are published in PNAS .
"Tumor cells comprise a significant proportion of the tumor microenvironment but are often under-utilized for immunotherapy," said corresponding author Natalie Artzi, PhD , a researcher in the Mass General Brigham Department of Medicine. "These findings highlight how tumor cells can be used to actively contribute to their own elimination."
The presence of double-stranded DNA (dsDNA) in a cell's cytoplasm activates innate immune sensors that set off defense mechanisms against potential infections or cellular damage. One such sensor known as cyclic GMP-AMP synthase (cGAS) detects cytosolic dsDNA and produces cyclic GMP-AMP (cGAMP), which triggers the stimulator of interferon genes (STING) pathway and leads to inflammatory immune responses. Furthermore, cGAMP can be transported out of the cell to activate neighbouring cells. While cancer cells can have high levels of cytosolic dsDNA, they often silence the cGAS-STING pathway — preventing their own activation and of bystander immune cells within the tumor microenvironment.
The research team exploited this innate mechanism within cancer cells to increase cGAMP production and thereby boost antitumor immunity. They found that cultured mouse melanoma cells upregulated cGAMP production when treated with dsDNA and lipid nanoparticles (LNPs) carrying mRNA coding for cGAS. Immune cells showed signs of activation in response to elevated extracellular cGAMP levels produced by cancer cells. Similarly, treatment with cGAS LNPs activated surrounding immune cells, slowed tumor growth and improved overall survival in mouse models of aggressive melanoma. Combining this treatment with immune checkpoint blockade therapy further improved outcomes.
The authors suggest that this strategy could find future applications beyond cancer therapies, including in vaccines.
Authorship: In addition to Artzi, Mass General Brigham authors include Alexander M. Cryer, Pere Dosta, Michelle Z. Dion, Leonardo de la Parra Soto, Eliz Amar-Lewis, Gabriela Garcia de Leon, Alejandro Espinosa Perez, Diego Fernando Ruiz Aguilar, Triana Huerta, Beatriz Nicolas Ruiz and Nathalie Nicole Casteele Hernandez.
Paper cited: Cryer, A M et al. "Restoration of cGAS in tumor cells promotes antitumor immunity via transfer of tumor-cell generated cGAMP" PNAS DOI: 10.1073/pnas.2409556122
