Lung cancer takes over the brain to trick the immune system
Lung cancer tumor cells in mice communicate with the brain, sending signals to deactivate the body’s immune response, a study has found.
Lung cancer at the left pulmonary lobe, seen on radial section MRI scan of the chest.
BSIP/Universal Images Group via Getty Images
For years, scientists have viewed cancer as a localized disorder in which cells refuse to stop dividing. But a new study shows that, in some organs, tumors actively communicate with the brain to help protect them.
Scientists have long known that nerves develop in some tumors and that tumors that have a lot of nerves generally have a worse prognosis. But they didn’t know exactly why. “Prior to our study, most of the focus has been on this local interaction between nerve[endings]and the tumor,” says Chengcheng Jin, assistant professor of cancer biology at the University of Pennsylvania and co-author of the study, which was published today. Nature.
Jin and his colleagues discovered that lung cancer tumors in mice can use these nerve endings to communicate beyond their immediate area and send signals to the brain. through a complex neuroimmune circuit. They also confirmed that the circuit exists in humans.
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The establishment of this circuit begins with a process called innervation, in which lung tumors wire themselves into the vagal nerves – the internal information highway that connects vital organs to the brain. Within this highway, Jin’s team identified a particular group of sensory neurons that communicate directly with the central nervous system. “Our study shows that tumors actually hijack these existing pathways to promote themselves,” explains study co-author Rui Chang, associate professor of neuroscience at Yale School of Medicine.
When a tumor grows, it employs vagal neurons to send signals to the nucleus of the solitary tract – the area in the brain stem that, under normal circumstances, controls functions such as blood pressure, heart rate or digestion. The signal sent by the tumor exploits this system, just like malicious code used by a hacker.
Instead of recognizing the tumor as an invader that needs to be destroyed, the brain processes the signal and activates the sympathetic nervous system, known primarily as the driver of the fight-or-flight response. This sympathetic surge causes the release of noradrenaline, which has devastating consequences in the context of cancer.
Noradrenaline is released directly into the immediate neighborhood of the tumor, where it binds with macrophages – the frontline cells of the immune system that recognize, eat and destroy threats. Macrophages attach to docking stations called β2 adrenergic receptors, which normally tell cells when to be aggressive and when to “chill out,” preventing the immune system from destroying healthy cells. When noradrenaline released by brain-controlled nerves binds to these receptors, it effectively reprograms the macrophages to switch sides.
In this suppressed state, they begin to release chemical signals that act as a “do not disturb” signal to the rest of the immune system. It disables one of the body’s most effective weapons: T cells, specialized killers that physically kill tumor cells. Because the brain has ordered macrophages to form an immunosuppressive shield, T cells lose their energy, stop multiplying and fail to recognize the cancer as a threat.
“The authors have characterized an entire bidirectional tumor-nerve pathway that promotes tumor growth with great relevance to human health,” says Katherine Dulac, professor of molecular and cellular biology at Harvard University, who was not involved in the study.
Jin and his team also looked for ways to prevent tumors from talking to the brain. By mapping this loop from the lungs to the brain and back again, the researchers identified several new places where they could “cut the wire.” The study showed that blocking any part of the brain-tumor circuit reawakens the immune system.
“Clearly, the perspective of application to cancer treatment is extremely promising,” says Dulac. However, Jin and Chang say we are still a long way from translating their findings into therapeutic strategies.
“What we’re talking about is going from a mouse model to a human. I think there’s still a very long way to go,” says Chang.
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