How cancer and immune cells communicate

David Klinke, a researcher with the West Virginia University School of Medicine and Cancer Institute, is deciphering the contents of exosomes that cancer cells release. Studying the information exosomes contain and how they influence other cells may suggest new targets for cancer immunotherapy.

"Exosomes are like little balls of information relayed between cells," said Klinke, an associate professor in the Benjamin M. Statler College of Engineering and Mineral Resources.

They house multiple proteins, which are the building blocks of cells. They also contain RNAs that provide instructions for making new proteins and manipulate what genes do.

"If we imagine that an individual protein is like a sentence, then an exosome is like an entire book," he said.

Not just the 'garbage can of the cell'

Klinke and his colleagues wanted to learn how the "books" of information that tumor cells send out might interfere with our body's ability to detect and battle tumors. But first they had to find out what the cancer cells were stashing in their exosomes to begin with.

So, they collected exosomes secreted by melanoma, a type of cancer that strikes pigment-producing cells, and identified the types of proteins and RNA they contained.

The researchers discovered that the melanoma cells seemed to selectively package certain proteins and RNAs in their exosomes while withholding others. This finding contradicted the long-held assumption that exosomes contain a random assortment of the cell's contents.

"Early on it was thought that exosomes were kind of the garbage can of the cell, where everything in it was a representation of what's in the cell," Klinke said. "In the last 10 years or so, there's been a re-recognition of exosomes. Folks have gone back to the literature and realized they'd seen these things before but didn't really know what they did. More recently, researchers have been able to separate them out and figure out ways to isolate them. Now we're at the stage of, 'Well, what do they do? What role do they play in cell communication?'"

Subduing the immune response

Next, the team stimulated T cells -- a type of immune cell that detects and destroys invaders -- so that, under normal conditions, they would recognize melanoma and kill it. Klinke likens the process to getting a flu shot.

"Each T cell recognizes a unique pattern," he said. "This is why you get the flu vaccine. You want to pre-activate those T cells to recognize certain patterns that we expect to see in this year's flu."

Initially, when the researcher exposed the T cells to melanoma, the T cells responded as expected: they quickly multiplied to swarm the cancer. But once the researchers added melanoma exosomes to the sample, "the T cells stopped proliferating," Klinke said. "The exosomes essentially suppressed their response."

The results were published in FEBS Journal, the international journal of the Federation of European Biochemical Societies, in 2018. This year, Klinke and his colleagues -- Christina Byrne-Hoffman, Cassidy Bland, Audry Fernandez, Stephanie Rellick and Wentao Deng -- won FEBS' Richard Perham Award for the publication. FEBS invited them to present their findings at the FEBS Congress in Krakow, Poland, this summer.

The team's results indicate that cancer cells may use their exosomes to avoid eradication by subduing T cell activity.

"Exosomes create an environment for tumor cells to survive," Klinke said. "If an exosome is a book of information, it influences how the immune system reacts to its environment. But, if we look at how the immune system reads the information and how that influences the T cell, maybe we could engineer immune cells to ignore or dispose of exosomes that they encounter."