New light-activated method precisely targets cancer and inflammatory cells

A new method of precisely targeting troublesome cells for death using light could unlock new understanding and treatments for cancer and inflammatory diseases, University of Illinois Urbana-Champaign researchers report.

Inflammatory cell death, known as necroptosis, is an important regulatory tool in the body’s arsenal against disease. However, in some diseases, the process can go awry. for example, cancer cells are able to suppress inflammatory signals and thus escape death.

Usually cancer treatments use pharmacological induction to kill cells, but these chemicals tend to spread throughout the tissues and are difficult to contain in a precise location. You have many unwanted effects. We can make cells respond to light and we can focus the light beam to be smaller than a cell. So we can use light to very precisely target a cell and activate its death pathway.”

Kai Zhang, study leader, professor of biochemistry at the U. of I

Researchers use a method called optogenetics to make cells respond to light. They borrowed a light-activated gene from plants and introduced it into intestinal cell cultures, attaching it to the RIPK3 gene, a protein that regulates necroptosis.

“When activated, RIPK3 undergoes oligomerization—it forms clumps of protein complexes. Our photosensitive proteins aggregate when exposed to blue light. So by triggering the photosensitive proteins to come together, RIPK3 comes together and oligomerizes, and that’s how we mimic the activation pathway,” said graduate student Teak-Jung Oh, its first author paper was published on Journal of Molecular Biology.

However, killing the cell itself is not the only goal. Inducing the inflammatory cell death pathway, rather than completely 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 an important role in how the immune system detects and attacks threats, Zhang said.

“Certain types of cancer cells create a local immunosuppressive environment where T cells are either not recruited or, if they do come, do not recognize it as a threat and do not infiltrate the tumor area. But by opening up certain cancer cells through necroptosis, we hope to modulate this immunosuppressive environment and help train T cells to recognize and attack cancer,” said Zhang, of the Illinois Cancer Center.

Since the optogenetic system requires light delivery directly to tissues, human clinical applications in tissues deeper than the skin are currently limited. However, the Illinois team plans to apply their system to mice to further study necrosis and the immune response in cancer and other inflammatory diseases. They will also further explore the platform’s potential in vitro for training T cells for immunotherapies.

“Understanding the cellular signaling pathway for necrosis is particularly important because it is known to be involved in diseases such as neurodegenerative disease and inflammatory bowel disease. It is important to know how necrosis affects progression in these diseases. And if you don’t know the molecular mechanisms, you don’t really know what to target to slow 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 Illinois Cancer Center supported this work. Zhang is also affiliated with the Beckman Institute for Advanced Science and Technology in Illinois.