Light targets the death of cells and triggers

CHAMPAIGN, Ill. — A new method of targeting problem cells with light could lead to a new understanding of cancer and inflammatory diseases and new treatment options, researchers at the University of Illinois Urbana-Champaign report.

Inflammatory cell death, also called necroptosis, is an important regulatory mechanism in the body’s fight against disease. However, in some diseases this process can get out of control. Cancer cells, for example, are able to suppress inflammatory signals and thus avoid death.

“Cancer treatments typically use pharmacological induction to kill cells, but these chemicals diffuse throughout tissue and are difficult to pinpoint to a precise location. There are many unwanted side effects,” said study leader Kai Zhang, a professor of biochemistry at the University of Illinois. “We can make the cells sensitive to light and focus the light beam so that it is smaller than a cell. This allows us to use light very precisely to target a cell and turn on its death pathway.”

The researchers used a method called optogenetics to make the cells respond to light. They took 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 clump together when exposed to blue light. So by stimulating the light-sensitive proteins to associate, RIPK3 comes together and oligomerizes, and so we mimic the activation pathway,” said graduate student Teak-Jung Oh, the first author of the paper published in The 40th Annual Journal of Neuroscience. Journal of Molecular Biology.

But killing the cell itself is not the only goal. Inducing inflammatory cell death, rather than directly killing the cell mechanically or chemically, triggers an immune system response. The destroyed cells release chemicals called cytokines that irritate neighboring cells and attract T cells, white blood cells that play an important role in identifying and fighting immune system threats, Zhang said.

“Certain cancer cell types create a local immunosuppressive environment where T cells are either not recruited or, if they do come, do not recognize them as a threat and do not invade the cancer area. However, by opening up some cancer cells through necroptosis, we hope to modulate this immunosuppressive environment and train the T cells to recognize and attack the cancer,” said Zhang, who is a member of the Cancer Center at Illinois.

Because the optogenetic system requires direct light delivery to the tissue, clinical applications in humans in tissues deeper than the skin are currently limited. However, the Illinois group plans to use their system in mice next to further study necroptosis and immune responses in cancer and other inflammatory diseases. They will also further investigate the potential of the in vitro platform to train T cells for immunotherapies.

“Understanding the cell signaling pathway for necroptosis is particularly important because it is known to be associated with diseases such as neurodegenerative diseases and inflammatory bowel disease. 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 attack to slow the progression,” Oh said.

This work was supported by 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 at Illinois. Zhang is also affiliated with the Beckman Institute for Advanced Science and Technology in Illinois.

Editor’s note: To reach Kai Zhang, email [email protected].

The article “Spatiotemporal control of inflammatory lytic cell death through optogenetic induction of RIPK3 oligomerization” is available online. DOI: 10.1016/j.jmb.2024.168628

The National Institutes of Health supported this work through grants R01GM132438 and R01MH124827.