Orchestrating an immune response, either by turning the immune system on or switching it off, is one of the biggest, hottest fields in drug R&D. And now a team of investigators at UC Davis say that they discovered a mechanism that may help research into immuno-oncology as well as autoimmune conditions like multiple sclerosis.
To activate CD4 T cells and turn them into cancer fighters--a field that is consuming hundreds of millions of research dollars each year--researchers rely on a cascade of events, the researchers note. The T cells have to recognize antigens on the surface of the target, get a boost from costimulatory signals and then encounter cytokines--such as IL-2--that amp up the assault.
But if you scramble that approach, they add, and get cytokines involved too early, you shut down the CD4 T cell attack before it even begins. That's a problem that will need to be considered by scientists involved in developing the first wave of immune-oncology drugs, as well as investigators who can use this target for shutting down autoimmune responses, when the immune system attacks healthy tissue.
"These stimulatory immunotherapies are designed to activate the immune system," said first author Gail Sckisel, "but considering how T cells respond, that approach could damage a patient's ability to fight off pathogens. While immunotherapies might fight cancer, they may also open the door to opportunistic infections."
The researchers studied the effect in mice and then verified it in samples taken from melanoma patients.
"We need to be very careful because immunotherapy could be generating both short-term gain and long-term loss," noted lead author William Murphy, professor and acting chair in the UC Davis Department of Dermatology. "The patients who were receiving immunotherapy were totally shut down, which shows how profoundly we were suppressing the immune system."
- here's the release