Reprogramming Traitors with Nanotechnology

Reprogramming Traitors with Nanotechnology

New finding may lead to a new therapy for aggressive ovarian cancer

José R. Conejo-Garcia, M.D., Ph.D.Admittedly, it sounds like a dark sci-fi plot, possibly starring Keanu Reeves: “reprogram” treacherous double agents using nanotechnology — synthetic, engineered molecules — designed to silence a specific gene.

According to Wistar’s José R. Conejo-Garcia, M.D., Ph.D., the scenario is not only real, it’s happening. Recently, his laboratory identified the traitorous cells of our own immune system that help ovarian cancers become so aggressively metastatic. Fortunately, his laboratory has also developed a tool to win back the allegiance of these cells and restore their ability to suppress tumors.

“Ovarian tumors don’t necessarily break ‘free’ of the immune system, rather dendritic cells of the immune system seem to actively support the tumor’s escape,” said Conejo-Garcia, a Wistar associate professor and leader of the newly-formed Tumor Microenvironment and Metastasis Program in Wistar’s Cancer Center. “More importantly, we show that by depleting these dendritic cells of the immune system, we can reverse the effect.”

This winter, in the Journal of Experimental Medicine, Conejo-Garcia presented the first successful attempt to reproduce the tumor microenvironment of human ovarian cancer in a mouse model of the disease. In essence, the model replicates the inflammatory surroundings that ovarian tumors experience in humans, providing a better tool for researchers to understand, prevent, and treat tumors.

With support from National Cancer Institute and the U.S. Department of Defense, the Conejo-Garcia laboratory combines emerging tumor microenvironment science and the latest molecular tools to combat ovarian cancer, one of the most deadly forms of cancer in women.

What they found confirmed their suspicions that, within the ovarian tumor microenvironment, a traitor lurked. In healthy tissue, dendritic cells function as sort of alarm system to alert the immune system to potential threats. They work as antigen-presenting cells, offering foreign or disease-causing molecules (called antigen) to the white blood cells that can then respond to an infection or, in this case, tumorous growths. Amid the ovarian cancer microenvironment, dendritic cells induce the immune system to attack tumor cells and inhibit their growth.

Except, Conejo-Garcia found, there comes a point where dendritic cells may switch sides and actively encourage tumors to spread.  
“We see a change in the dendritic cells themselves, which allows tumors to progress to terminal disease in a very short time,” Conejo-Garcia said. “Interestingly, the tumors are still immunogenic — they could still otherwise elicit an immune response — it is just that the dendritic cells are actively suppressing the involvement of other anti-tumor immune cells, primarily T cells.”

Conejo-Garcia and his colleagues believe that their findings offer a twist on the emerging theory of “cancer immunoediting.” In immunoediting, the immune system actively “edits” tumors to eliminate the individual cancer cells that express recognized antigen, thereby preventing small tumors from becoming symptomatic. All symptomatic tumors, therefore, represent a failure of the immune system, where tumors lose their immunogenicity — their ability to trigger and be recognized by our immune system.

According to Conejo-Garcia, these findings presented a new strategy to treat metastatic ovarian cancer. If they could somehow target these traitorous dendritic cells, it may effectively “reactivate” anti-tumor T cells.

Putting theory to the test

Indeed, this winter, in the journal Cancer Research, the researchers demonstrated how artificial RNA molecules could
win back the allegiance of dendritic cells and restore immunoediting.

For years, the Conejo-Garcia laboratory has explored methods of using nanoparticles — synthetic molecules built at the same billionth-of-a-meter scale on which proteins and genes operate — for therapeutic effect. In this instance, they built a nanoparticle that carries a replication, somewhat, of a form of  “micro-RNA” called miR-155.

As the name implies, micro-RNA are small snippets of RNA molecules. One of the central tenets of biology is that RNA carries the instructions encoded as genes within segments of DNA to the cell’s protein-making machinery. As scientists have found out over the last decade, not all RNA molecules are fated to serve as operating instructions for protein factories. So-called silencing RNA, like miR-155, can serve to turn off genes by binding to DNA and, in effect, smothering individual genes to prevent them from being read or expressed into protein.

Previous research has shown that miR-155 has a distinct role in maintaining the immunoediting of ovarian cancer, so the Conejo-Garcia laboratory went about developing nanoparticles that carried segments of RNA-mimicking miR-155 to test their effect. According to Conejo-Garcia, their nano-RNA molecules restored dendritic cell function in their ovarian cancer mouse model.

“For us, this is a one-two proof of concept in that we can see further evidence that our model works and we have a path for developing a potential new drug for aggressive ovarian cancer,” Conejo-Garcia said. “We are beginning to see this remarkable world where we can silence individual genes for therapeutic effect.”

In essence, turning science fiction into medical reality. Or, to quote Keanu Reeves: “Whoa.”