Genetically engineering skin bacteria to fight cancer

While studying a type of bacteria that lives on the healthy skin of every human being, researchers from Stanford Medicine and a colleague may have stumbled on a powerful new way to fight cancer.

After genetically engineering the bacteria, called Staphylococcus epidermidis, to produce a tumor antigen (a protein unique to the tumor that's capable of stimulating the immune system), they applied the live bacteria onto the fur of mice with cancer. The resulting immune response was strong enough to kill even an aggressive type of metastatic skin cancer, without causing inflammation.

It seemed almost like magic. These mice had very aggressive tumors growing on their flank, and we gave them a gentle treatment where we simply took a swab of bacteria and rubbed it on the fur of their heads."

Michael Fischbach, PhD, associate professor of bioengineering

Their research was published online April 13 in Science. Fischbach is the senior author, and Yiyin Erin Chen, MD, PhD, a former postdoctoral scholar at Stanford Medicine, now an assistant professor of biology at the Massachusetts Institute of Technology, is the lead author.

Skin colonizers

Millions of bacteria, fungi and viruses live on the surface of healthy skin. These friendly colonists play a crucial role in maintaining the skin barrier and preventing infection, but there are many unknowns about how the skin microbiota interacts with the host immune system. For instance, unique among colonizing bacteria, staph epidermidis triggers the production of potent immune cells called CD8 T cells — the "killer" cells responsible for battling severe infections or cancer.

The researchers showed that by inserting a tumor antigen into staph epidermidis, they could trick the mouse's immune system into producing CD8 T cells targeting the chosen antigen. These cells traveled throughout the mice and rapidly proliferated when they encountered a matching tumor, drastically slowing tumor growth or extinguishing the tumors altogether.

"Watching those tumors disappear — especially at a site distant from where we applied the bacteria — was shocking," Fischbach said. "It took us a while to believe it was happening."

The mystery of the T cells that do nothing

Fischbach and his team didn't start out trying to fight cancer. They wanted to answer a much more basic question: Why would a host organism waste energy making T cells designed to attack helpful colonizing bacteria? Especially as these T cells are "antigen-specific," meaning each T cell has a homing receptor that matches a single fragment of the bacterium that activated it.

Even stranger, the CD8 T cells induced by naturally occurring staph epidermidis don't cause inflammation; in fact, they appear to do nothing at all. Most scientists thought colonist-induced T cells must be fundamentally different from regular T cells, Fischbach said, because instead of traveling throughout the body to hunt for their target, they seemed to stay right below the skin surface, somehow programmed to keep the peace between bacteria and host.

To test whether these colonist-induced CD8 T cells could behave like regular killer T cells, the researchers engineered a strain of staph epidermidis to produce a different antigen — one that would generate T cells specific for a commonly studied tumor model in mice.

They genetically grafted a small fragment of DNA encoding part of a protein called ovalbumin onto the surface of staph epidermidis. They chose ovalbumin because it's been engineered into many commonly studied mouse tumor lines, including a type of aggressive melanoma, and therefore can act as a tumor antigen in multiple types of cancer. 

The power of tumor-specific T cells

Next, the scientists applied the genetically engineered bacteria to healthy mice. Because staph epidermidis is an efficient skin colonizer, they didn't need to clean or shave the animals' fur, but simply rubbed the bacteria on their heads. As expected, colonization didn't cause any inflammation or infection.