'Exciting' Progress in Cancer Research Makes Tumor Cells Easier to Destroy

Scientists in California made a surprise discovery that could revolutionize the way we treat cancer.

The researchers from the Salk Institute in San Diego have revealed a new pathway to improve the body's ability to recognize and fight cancer cells, promising to make immunotherapy accessible to a wider range of patients. Their results were published Thursday in the journal Science.

"You can think of immunotherapy as a pro-drug," Susan Kaech, the paper's co-senior author and director of the NOMIS Center for Immunology and Microbial Pathogenesis, told Newsweek. "[It] uses your body's adaptive immune system to fight the tumor."

Immunotherapy has several key benefits over traditional chemotherapy. "It's a versatile and highly diversified toolkit," Kaech said. "Although there are certainly side effects, immunotherapy is overall less toxic compared to chemotherapy and easier for the patient to handle.

"The most important difference, though, is that because immunotherapy elicits an adaptive immune response to the tumor, patients can develop a long-term immunological memory [to recurring tumors.]"

However, immunotherapy does not work for everyone.

"Immunotherapy can be really, really effective but it also only works generally in a minority of people, and it's really not clear what the reasons for that are," Payam Gammage, a senior lecturer and expert in mitochondrial oncogenetics at the University of Glasgow and a group leader at Cancer Research UK Beatson Institute, told Newsweek.

"It's a really exciting area, and lots of people are trying to find different ways to make immunotherapy work in more people," he said.

One indicator as to whether a patient will respond to immunotherapy is the state of their mitochondria—the energy-producing powerhouses of the cell.

"If you take patients and stratify them by whether they have mitochondrial deficiencies or not in their tumor, that is a very powerful way to predict who will respond to immunotherapy or not," Gammage said.

In the past, mitochondria were often discounted as having an unimportant role in cancer. However, in the last few years, new research has challenged this assumption.

"Mitochondria play a multifaceted role in cancer, contrary to some initial ideas that they are switched off and redundant to cancer development," Tom MacVicar, an expert in mitochondrial reprogramming in cancer also at the University of Glasgow and Cancer Research UK Beatson Institute, told Newsweek.

"For instance, they drive the biosynthesis of macromolecules (like fats and the building blocks of DNA) which are essential for cancer cell growth and proliferation. They are also important for cancer cell survival in harsh microenvironments and in response to anti-cancer therapeutics. They regulate [the internal balance of cells], cell death pathways, inflammatory pathways and more."

And so, Kaech, together with the lab of Gerald Shadel of the San Diego Nathan Shock Center of Excellence in the Basic Biology of Aging, decided to investigate how changes to these cellular powerhouses could impact tumor growth.

In addition to uncontrollable growth, one of the hallmarks of cancer cells is their ability to evade the immune system of their hosts.

"I call this the double whammy," Kaech said. "That was really the crux of this study—to better understand how tumors acquire the metabolic state that gives them a growth advantage as well as an ability to evade the immune system. And the mitochondria was a big focus because of its role in metabolism."

However, what they found was totally unexpected.

"The major discovery of our paper was serendipitous," Kaech said. "It was one of those moments when the reasons for doing your experiments are very sound but then what you get out of them is quite unexpected and exciting."

In their study, Kaech, Shadel and their lab members rewired mitochondria to restrict the flow of energy through their internal molecular machinery. This resulted in the build-up of a metabolite called succinate.

Succinate has many roles throughout the cell, including regulating gene expression. So by increasing the concentration of succinate in the cell, the researchers were able to increase the expression of certain genes involved in cross-talk with the immune system.

As the "policeman" cells of the immune system patrol our bodies, our cells display a range of molecules on their surfaces, which act as a sort of molecular ID to indicate that they are healthy. These molecules are randomly sampled from the interior of the cell and are held up by special structures on the cell's surface called MHC glycoproteins.

Rewiring the mitochondria to produce higher levels of succinate results in an increased number of these MHC glycoproteins on the surface of the cell, meaning more sampling can be done of the cell's interior. This means that if there are any dodgy mutations floating around inside the cell, they are more likely to get picked up by the immune system. In other words, it becomes harder for the tumor cells to evade our immune systems.

"These subtle changes basically turn the tumor into something that can be recognized by the immune system," Kaech said. "That could have a very big impact in the field [of immunotherapy]."

Exactly how this mitochondrial rewiring would be targeted to tumor cells is still a challenge. "If you give that drug systemically to the person then you're obviously going to have serious toxicity problems," Gammage said. "We need to find a way to use this information to make it actionable. That's the big challenge and it's an active area of research."

Luckily, Kaech said that these specific metabolites can be delivered to the cell in different ways, offering several potential avenues for drug delivery.

"We showed that we could supply succinate to the cells externally and get the same effects, so the succinate could come from outside or inside the cell," Kaech said.

While more work needs to be done to translate these findings into clinical practice, the discovery offers an exciting new avenue for future treatment solutions.

"These are really exciting times and a really cool potentially therapeutically usable approach," Gammage said.