Investigators at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine report a promising strategy that could help the immune system recognize tumor cells as different and dangerous, mount an immediate attack, and remove them as efficiently as it does with cells infected with threatening viruses or bacteria.
“This is a new therapeutic concept that enables us to understand why tumor cells are so immunologically inert,” said Glen N. Barber, Ph.D., Eugenia J. Dodson Chair of Cancer Research at Sylvester and professor and chair of the Miller School’s Department of Cell Biology.
Barber and his team took it a step further and devised a mechanism to make tumor cells easily recognizable by the immune system. An article, “Extrinsic Phagocyte-Dependent STING Signaling Dictates the Immunogenicity of Dying Cells,” detailing their methodology was published online April 26 in the prestigious journal Cancer Cell.
The study suggests that the intervention can “cure” the mice long-term, as well.
“We re-challenged the mice who survived with the same aggressive tumors — and all of them were protected,” Barber said.
It starts with death. When a normal cell in the body dies, which happens millions of times a day, the phagocytes of the immune system swoop in, “digest” the cell, and remove it, including the DNA or nucleic acid. The process works because phagocytes have enzymes called DNases that break down the DNA into smaller, more digestible pieces.
In contrast, when a cell containing viral, bacterial or other pathogenic nucleic acid dies, the foreign genomic material accumulates in the cytosolic compartment of the cell that does not contain many nucleases. This creates a very different scenario.
“It’s like a no-go zone for DNA,” Barber said, explaining that the cytosol of a cell does not normally contain DNA. However, “the majority of the innate immune sensors, including STING [for stimulator of interferon genes], are in the cytosol.”
The presence of cytosolic DNA usually means that the cell has been infected, or that the cell has undergone DNAdamage, which causes the formation of cytoplasmic nuclei. Both these events activate STING and cytokine production to alert the immune system, including phagocytes that remove the cells.
“Following phagocytosis, a virus-infected cell that is dying stimulates a massive immune response compared to an uninfected dying cell,” Barber said.
Because viruses and bacteria replicate their genomes to high levels within the cell, these dying cells contain enormous amounts of microbial nucleic acids that can overwhelm the nucleases in the phagocyte. The release of substances called cytokines then facilitates the production of anti-tumor or microbial cytotoxic or “natural killer” T cells.
Transfecting Tumor Cells
So how could the normal immune process for eradicating cells infected with viruses or other dangerous microbes help rid the body of tumor cells? Barber and team hypothesized that injecting synthetic DNA into the cytosol of mouse tumor cells could mimic an infected or DNA-damaged cell and stimulate the immune reaction.
“We had a hunch it might work,” Barber said.
And it did.
“If you feed a phagocyte a cell that is carrying our synthetic DNA, it appears to mimic a virus infection and it goes absolutely crazy,” Barber said. “So we can make a ‘cold’ tumor ‘hot’ now.”
To prove their theory, Barber and colleagues introduced an aggressive form of metastatic cancer to mice with immune systems, a move that would otherwise kill the mice within 20 to 30 days. But they then therapeutically treated the mice with the same tumor cells full of the synthetic DNA.
“We could rescue and cure 40 percent to 60 percent of the animals just by this simple treatment. And this is without using any checkpoint inhibitors or any other cancer-fighting therapy,” said Barber. “We found out these cells were eaten in vivo by phagocytes, which stimulated the production of anti-tumor T cells in sufficient numbers to actually cure a reasonable percentage of the mice. And that’s very hard to do.”
Moreover, the immune effect was dependent on the innate sensor STING, originally discovered by the Barber lab.
Miller School of Medicine