Pyroptosis (not pictured above) is like an explosion — a self-destruction that attracts other immune cells to fight the infection.
Despite several immunotherapy drugs gaining FDA approval to treat multiple cancers, these therapies do not work in every patient. In light of this, researchers are continuously searching for new ways to activate the immune system and make such treatments more widely effective.
One drug, called Val-boroPro, has intrigued scientists for nearly a decade because it has been shown to shrink tumors in mice and “immunize” them against future cancers. But there was one hitch: For years, nobody could quite figure out how it works.
A team led by Daniel Bachovchin, a chemical biologist in the Sloan Kettering Institute (SKI), has discovered that Val-boroPro activates the immune system to attack through a form of highly inflammatory programmed cell death called pyroptosis. This finding, reported in Nature Chemical Biology, could help researchers unravel how various immune system components interact, using Val-boroPro as a tool.
Pyroptosis occurs in immune cells called monocytes and macrophages. It usually is induced when a pathogen (such as a bacterium or virus) infects these cells, in part to hide from immune detection. In response, the cells swell, burst, and die, releasing pro-inflammatory signaling molecules. This self-destruction also releases the pathogens back into the surrounding environment and attracts other immune cells to fight the infection.
Although pyroptosis had been studied extensively, researchers had never seen a small molecule drug induce this form of cell suicide. Uncovering this cause and effect opens the door to a range of new research and therapeutic applications.
“Not only does this give us something that could be a therapeutic tool, it reveals an element of the biology that we didn’t know existed,” Dr. Bachovchin says.
“Off-Target” Proteins as the Key
Dr. Bachovchin’s laboratory in SKI’s Chemical Biology Program studies a group of enzymes called serine proteases and the roles they play in cancer and immune system signaling. Serine proteases are involved in a large number of biological processes and are needed for cell growth. They also are easy to block with drugs for potential therapeutic purposes. (One serine protease called DPP4 has been targeted with drugs for the treatment of type 2 diabetes.)
Val-boroPro was originally designed to inhibit DPP4, but it also blocks several additional serine proteases, including DPP8 and DPP9. And it’s that blocking of DPP8 and DPP9 that Dr. Bachovchin and his colleagues discovered ultimately causes pyroptosis through the activation of an enzyme called pro-caspase-1.
“If DPP8 and DPP9 are active, they appear to be constantly preventing pyroptosis from occurring and acting as a check on this type of immune response,” he says. “When you inhibit them, it triggers this type of cell death, inflammation, and immune attack. We’re going to highlight what else these enzymes do — which is clearly of profound biological consequence.”
An important next step will be designing new drugs that selectively inhibit only DPP8 and DPP9 to reduce toxic effects resulting from hitting other targets, Dr. Bachovchin says. Researchers also aren’t sure whether inhibiting DPP8 and DPP9 will itself be sufficient to induce a strong enough anti-cancer immune response.
“Although much of our other research is in an early stage, this finding is going to frame a lot of downstream work,” Dr. Bachovchin says. “This gives us molecular control over one part of the immune system to start answering important questions.”
