NTUH-linked study shows how lung cancer uses nerves to weaken immunity

Taipei, July 8 (CNA) An international research team with Taiwanese participation has identified a previously unknown mechanism by which lung cancer activates sensory nerves to weaken the body's immune response, a finding that could offer a new path for cancer treatment.

The study "uncovered a neuro-immune regulatory mechanism in lung cancer" and could lead to a new cancer treatment direction based on "cutting off the electricity" to tumors, said Chen Jin-shing (陳晉興), head of National Taiwan University Hospital's (NTUH) Department of Surgery, referring to blocking nerve signals that help cancer grow.

Chen said at a press conference in Taipei that no research team had previously published findings on whether neuro-immune modulation -- the idea of "cutting off the electricity" to cancer -- could make treatment more effective.

The stakes are high because "lung cancer has been the leading cause of cancer deaths in Taiwan for more than two decades," and it killed more than 10,000 people in Taiwan last year alone, Chen said, citing Ministry of Health and Welfare data.

Among the different types of lung cancer, he said lung adenocarcinoma remains a major concern because it accounts for more than 70 percent of cases and still has a poor prognosis when diagnosed at an advanced stage.

Nerves that aid tumor growth

On hand to explain the mechanism the research team discovered was Leanne Li, head of the Cancer Neuroscience Laboratory at the Francis Crick Institute in the United Kingdom who earned a medical degree from National Taiwan University.

According to Chen, a team led by Li began working with NTUH and other international researchers several years ago to examine whether nerves around lung tumors could affect cancer progression.

Explaining the study's findings, Li said nociceptive sensory nerves normally detect danger signals in the environment and help coordinate corresponding immune responses.

For example, people may instinctively hold their breath when they smell something unusual or cough when exposed to smoke, she said.

"Our question was whether, if these environmental stimuli are considered danger signals, a tumor growing in the lung could also be seen by these nerves as a kind of danger signal," Li said.

The study found that as lung adenocarcinoma progresses, nociceptive sensory nerves around tumors become more active and release calcitonin gene-related peptide (CGRP).

CGRPs are often associated with migraine headaches, because when CGRP is released, it causes inflammation in the brain and headache pain, according to the website Migraine Australia.

Li said that in her team's study, the release of CGRP was found to prevent the formation of tertiary lymphoid structures (TLS) near tumors.

Those structures are immune-cell gathering sites that help the body organize attacks on cancer cells and are linked to better outcomes in lung adenocarcinoma patients.

Possible treatment direction

In mouse models, blocking the CGRP-related nerve signals restored TLS formation, strengthened anti-tumor immunity and slowed tumor growth, according to the study.

The team also found that cigarette smoke extract activated the same pathway, suggesting that smoking may promote lung cancer not only by causing gene mutations, but also by overstimulating pain-sensing nerves and thereby weakening the immune response around tumors.

In smoke-exposed mice, blocking CGRP with a drug targeting the same pathway as some migraine treatments made tumors more responsive to immunotherapy and prolonged survival, the study said.

Li said one of NTUH's main contributions to the study was providing lung adenocarcinoma samples from patients, allowing the team to verify that CGRP levels were higher in human lung tumors and examine whether CGRPs affected immune cells in the tumor microenvironment.

She added that clinical trials testing treatments based on the newly identified mechanism have not yet begun, but the team is now in discussions with hospitals in the United Kingdom about possible future studies and hopes to pursue a similar collaboration with NTUH.

The study, titled "Nociceptive innervation limits tertiary lymphoid structures to promote lung cancer," was published online in the top scientific journal Cell in mid-May and involved researchers from the Francis Crick Institute, NTUH, Harvard Medical School and Columbia University.