A new method of using light to precisely kill the cells that cause problems could lead to new insights into and treatments for cancer and inflammatory diseases, researchers from the University of Illinois Urbana-Champaign report.
Inflammatory cell death, known as necroptosis, is an important regulatory tool in the body’s arsenal against disease. In some diseases, however, the process can go haywire; for example, cancer cells are able to suppress inflammatory signals and thus escape death.
“Typically, cancer treatments use pharmacological induction to kill cells, but those chemicals tend to spread through tissues and it's hard to keep them in a precise location. You get a lot of unwanted effects,” said study leader Kai Zhang, a professor of biochemistry at the U. of I. “We can sensitize the cells to light, and we can focus the light beam so that it's smaller than a single cell. So we can use light to very precisely target a cell and turn on its death pathway.”
The researchers used a method called optogenetics to make the cells respond to light. They borrowed a light-activated gene from plants and inserted it into intestinal cell cultures, attaching it to the gene for RIPK3, a protein that regulates necroptosis.
“When activated, RIPK3 undergoes oligomerization — it forms clusters of protein complexes. Our light-sensitive proteins cluster together when they're exposed to blue light. So by triggering the light-sensitive proteins to come together, the RIPK3 comes together and oligomerizes, and we're mimicking the activation pathway,” said doctoral student Teak-Jung Oh, the first author of the paper published in the Journal of molecular biology.
Killing the cell itself isn’t the only goal, though. Inducing the inflammatory cell death pathway, rather than directly killing the cell mechanically or chemically, triggers the immune system to respond. The ruptured cells release chemicals called cytokines that irritate nearby cells and attract T cells, white blood cells that play a key role in how the immune system identifies and attacks threats, Zhang said.
“Certain cancer cell types create a local immunosuppressive environment where T cells are not attracted or, if they do get there, they don’t recognize it as a threat and don’t infiltrate the cancerous area. But by breaking up some cancer cells through necroptosis, we hope to modulate this immunosuppressive environment and help T cells recognize and attack the cancer,” said Zhang, who is a member of the Cancer Center of Illinois.
Because the optogenetic system must deliver light directly to tissues, clinical applications in humans in tissues deeper than the skin are currently limited. However, the Illinois group plans to implement their system in mice to further study necroptosis and immune response in cancer and other inflammatory diseases. They will also further explore the potential of the in vitro platform for training T cells for immunotherapies.
“Understanding the cell signaling pathway for necroptosis is especially important because it is known to be involved in diseases such as neurodegenerative diseases and inflammatory bowel diseases. It is important to know how necroptosis affects the progression of these diseases. And if you don’t know the molecular mechanisms, you don’t really know what to target to slow the progression,” Oh said.
The National Institute of General Medical Sciences and the National Institute of Mental Health of the National Institutes of Health, the National Science Foundation, and the Cancer Center of Illinois supported this work. Zhang is also affiliated with the Beckman Institute for Advanced Science and Technology in Illinois.
The National Institutes of Health supported this work through grants R01GM132438 and R01MH124827.
