From savoring a piece of cake to hugging a friend, many of life’s pleasures trigger a similar reaction in the brain—a surge of chemicals that tell the body “that was good, do it again.” Research published Friday in Nature Communications suggests this feel-good circuit may do much more. Using lab tools to activate that reward circuit in mice, scientists discovered that its chemical signals reach the immune system, empowering a subset of bone marrow cells to slow the growth of tumors. The findings have yet to be confirmed in humans. But given the reward system is linked with positive emotions, the research offers a physiological mechanism for how a person’s psychological state could help to stall cancer progression.
Plenty of research measures the health impact of stress and negative feelings, says Erica Sloan, a biologist at Monash University in Melbourne, Australia. But the potential for immune activity to shift in response to positive influences through the brain’s reward center—“that’s what I think is really exciting,” says Sloan, who studies neural-immune activity in cancer but was not involved in the present study.
The notion that the brain talks to the immune system isn’t new. One of the most compelling examples is the placebo effect—the centuries-old observation that sugar pills can work as well as evidence-based medicine in some people. For years scientists have tried to unravel the biology behind this mysterious phenomenon.
Clues emerged in brain imaging experiments published a decade ago. Those analyses revealed that the same reward circuit activated by food, sex and social interactions (as well as gambling and addictive drugs) is also turned on in people who respond to placebos. Puzzling over those data, researchers in Israel turned the mind-body question into an easier-to-measure physiological one: Would activation of the reward circuit have any effect on the immune system?
It seemed fair to assume positive thoughts and emotions would alter the activity of neurons in the brain. “And neuronal activity is something we can manipulate,” says biologist Asya Rolls of Technion-Israel Institute of Technology, who was co-senior author of the current study.
In previous work her team stimulated the brains of mice with a relatively new technology called DREADD (designer receptors exclusively activated by designer drugs) that puts a molecular on-off switch on particular cells—in this case, neurons of the reward circuit. After activating a mouse’s reward system, the researchers analyzed immune cells in its spleen. The clearest effects showed up in monocytes—a group of white blood cells that chew up pathogens as part of the body’s non-specific immune defenses. Specifically, the team found that monocytes from brain-activated mice killed bacteria much more effectively than monocytes from untreated animals.
Seeing that the brain’s reward circuit could boost immune activity against pathogens, “our next thought was, what is a situation where the immune system fails?” says Tamar Ben-Shaanan, a biologist now at the University of California, San Francisco who published the bacterial experiments in 2016. Ben-Shaanan and Technion MD-PhD student Maya Schiller are co-lead authors on the new study.
The idea of looking into cancer came from study co-senior author Fahed Hakim, who directs the EMMS Nazareth Hospital and works as a pediatric pulmonologist and sleep specialist at Rambam Health Care Campus in Haifa, Israel. During a research stint at the University of Chicago, Hakim studied mouse models of cancer and published a 2014 study showing that fragmented sleep made the animals’ tumors grow faster. If bad sleep triggers tumor-promoting brain activity, Hakim says, it seemed reasonable to think that activating the reward pathway might produce the opposite effect—brain changes that slow cancer.
And that’s what the researchers found. In mice with implanted cancer cells, two weeks of daily reward circuit stimulation produced a powerful response—their tumors were 40 to 50 percent smaller than those in control mice that didn’t get the brain activation. Further experiments traced this effect to a specific group of immune cells made in the bone marrow called myeloid-derived suppressor cells (MDSCs). If left unhindered, MDSCs promote tumor growth by shutting down other immune cells that keep tumors in check. However, activating the brain’s reward system unleashes chemical signals that thwart this web of checks and balances in a manner that disables these pro-tumor MDSCs. That, in turn, allows typical anti-tumor immune responses to proceed.
It’s like “doing immunotherapy without medication,” Hakim says, referring to a recent class of cancer drugs that work by equipping the patient’s own immune system to fight tumors.
David Spiegel, a psychiatrist at Stanford University who was not involved with the research, called it “an important and well-conducted study.” Previously Spiegel and colleagues showed that social support through weekly group therapy prolonged survival in women with metastatic breast cancer. Given the reward circuit is thought to be activated by positive thinking in the placebo effect, the new study offers a potential mechanism for “how good social support and gaining perspective on life in the face of death could have a positive effect on cancer survival,” Spiegel says.
Sloan’s group in Australia published earlier mouse studies showing that chronic stress targets the same immune cells influenced by reward circuit activation in the new paper. Taken together, her work and the new findings suggest that both positive and negative mental states can “push these immune cells around to the point that there’s an impact on cancer outcome.”
Rolls warns that the new mouse findings do not suggest cancer patients should quit taking medication and rely instead on positive thinking. They merely offer a possible mechanism for the latter’s purported benefits.
As a first step toward translating the findings from mice to humans, Rolls’ lab is collaborating with another group at Tel Aviv University to test if it’s possible to trigger immune effects by directly stimulating the reward circuit in people. Thus far the data are preliminary, Hakim says. But they raise the possibility that someday cancer patients could receive brain stimulation as an add-on therapy in conjunction with lesser amounts of traditional treatments such as chemotherapy and radiation.