Tumors Protect Themselves from Immune Attack by Talking to the Brain

A new Nature study shows how cancerous tumors help themselves grow by communicating with the brain.

In many tumors, nerves from our peripheral nervous system establish themselves in the cancerous tissue. The new study found that tumors can hijack these nerves to send signals to the brain. This, in turn, triggers activity that blocks immune cells from infiltrating the cancer, which enables cancer growth.

“Tumors are really smart,” says Chuyue Yu, a PhD student at Yale School of Medicine (YSM) and one of the study’s first authors. “They employ as many resources in the body they can get in touch with to promote their own growth.”

Principal investigator Rui Chang, PhD, associate professor of neuroscience and of cellular and molecular physiology at YSM, previously thought that the innervation of tumors could be bad for the cancer. He hypothesized that the nerves would detect them as invaders and send warning signals to the brain to remove the threat.

But to his surprise, his new study, done in collaboration with a team led by Chengcheng Jin, PhD, assistant professor at the University of Pennsylvania Perelman School of Medicine, revealed that disrupting sensory neurons in tumors caused them to shrink.

The team then sought to understand why this happens. Using animal models of lung adenocarcinoma, they experimented with inhibiting and activating various subpopulations of neurons to see how this impacted cancer growth. They also used single cell sequencing to identify the types of neurons innervating tumors in the lung, as well as imaging techniques to visualize how nerve and cancer cells interacted with one another. Meanwhile, collaborators at the University of Pennsylvania studied the surrounding immune cells and their signaling in the cancer microenvironment.

Through these techniques, the researchers discovered that tumors cause nerves to send signals to the brain, and that activates sympathetic nervous system activity—the part of the nervous system that drives “fight-or-flight” response. This, in turn, triggers the release of the hormone norepinephrine at the cancer site.

Norepinephrine activates specialized macrophages—immune cells that act as the body’s first line of defense—residing in the lung, which then block another type of immune cell called T cells from attacking the cancer. As a result, the cancer progresses unimpeded.

“The tumor promotes its own growth through this crosstalk to the brain that inhibits the immune environment,” says Chang, who is also a member of Yale's Wu Tsai Institute.

The study is one example of how tumors can adapt to a specific environment in a way that promotes its growth, he adds. Cancers can behave differently in various organs. And while some become significantly innervated, others have a total lack of innervation. His team is interested in exploring how different types of tumors communicate with the brain from different organs, which could help explain why some cancers act more aggressively.

The findings could also inform future therapies that target the parts of the nervous system underlying brain-tumor communication to halt cancer growth, the researchers say.

“Our study helps give a better understanding of how the brain, a massive computation organ, deals with the tumor,” Chang says. “There’s lots of potential to use this to fight tumor growth.”