Optogenetic Immunomodulation Reduces Cancer Tumor Size, Metastasis in Animal Model

Optogenetics has been modified for an immunotherapeutic approach that aims to kill cancerous tumor cells.

Neuroscientists have used light to stimulate neurons for years, said professor Yubin Zhou of Texas A&M University’s Health Science Center Institute of Biosciences & Technology. In neuroscience, optogenetics involves genetically engineering cells to produce proteins from light-sensitive microbes. The result is nerve cells that either send or stop sending nerve impulses when exposed to a particular wavelength of light.

Unlike nerve cells, immune cells don't communicate with electrical impulses; immune cells are also located deep in the body and are constantly moving around, so accessing them with light is a challenge in itself.

Now Zhou and his team have reported on a modified technique for the immune system — called optogenetic immunomodulation — that used a near-infrared (NIR) laser to penetrate deep (1 to 2 cm) into tissue, where lanthanide-doped upconversion nanoparticles converted the NIR light into blue light, which in turn directs the activity of genetically engineered immune cells towards kill tumor cells.

In a mouse model of melanoma using ovalbumin as a surrogate tumor antigen, the team genetically engineered immune cells so that a calcium gate-controlling protein became light sensitive. When they were exposed to the blue light emitted by the nanoparticle, their calcium ion gates opened. When the light was turned off, the gates close. More light led to a greater flow of calcium, so the researchers were able to finely tune the calcium-dependent actions of immune cells to fight against invading pathogens or tumor cells.

Schematic of optogenetic immunomodulation acting on a mouse model of melanoma. Courtesy of Yubin Zhou.
When the mouse model was injected with both the nanoparticle and the light-sensitive genetically engineered immune cells, the NIR laser beam caused calcium channels to open, which boosted an immune response to aid the killing of cancer cells.

"The technique reduced tumor size and metastasis, so there are lots of applications," Zhou said.

One advantage of this method is that it only activates a certain type of immune cell, the dendritic cell or T-cell, and only in one part of the body, near the draining lymph nodes or tumor. The researchers said these attributes cut down on the system-wide side effects often seen with chemotherapy.

The method is light-tunable, noninvasive and has high temporal resolution, meaning it can be turned on and off as needed.

This video clip shows light-triggered reversible cytosol-to-plasma-membrane translocation of a viral vector. Courtesy of Yubin Zhou.

"Other scientists will likely use the technique to help them study immune, heart and other types of cells that use calcium to perform their tasks," Zhou said. "It's quite a cool technology. With these tools, we can now not only answer fundamental questions of science that we never could before but also translate it into the clinic for disease intervention."

The research was published in eLife (doi: http://dx.doi.org/10.7554/eLife.10024).