Sensory nerve activity disrupts how immune cells are organised within lung tumours, weakening the immune response.
For Crick group leader Leanne Li, understanding cancer means looking beyond tumour cells to the signals that surround them.
“We’re starting to see the tumour microenvironment in all its complexity and what this means for disease progression,” she says. “It’s not just about which cells are present, but how they interact and communicate.”
Light-sheet image (a method that images whole tissue in 3D by illuminating thin layers with light) showing nerve fibres (green) in a mouse tumour.
The effectiveness of the immune response against cancer depends not just on immune cells being present, but how they are organised within the tumour microenvironment – the surrounding network of cells and signals that can either support or suppress immune activity.
Researchers have been investigating how different components of this environment shape disease progression, but one element has remained largely unexplored: the nervous system.
In a new study, published in Cell, Leanne and her team in the Crick’s Cancer-Neuroscience Laboratory, focused on the nervous system’s early warning mechanism - specialised sensory nerves that detect extreme thermal, physical or chemical threats and trigger protective responses in the body.
“In the presence of lung cancer, we see active growth of these nerves,” explains Ya-Hsuan Ho, co-first author and postdoctoral fellow. “We wanted to understand how tumours might be using these nerves, if they could hijack the nervous system.”
Ya‑Hsuan and co-author Giacomo Bregni set out to investigate what happens when sensory nerve activity is altered.
Using mouse models of lung cancer, they activated and deactivated these nerves in the lung, and used cell-based systems to examine how nerve-derived signals influence immune cells.
“We found that lung tumours increase both the length and activity of these nerves, and in turn that the increased neuronal activity was accelerating tumour growth,” adds Giacomo. “We were also able to trace this to increased levels of a chemical messenger called calcitonin gene-related peptide (CGRP).”
The team then interrogated how CGRP affects how immune cells are positioned within tumours.
“In the presence of this signal, immune organisation broke down,” describes Ya‑Hsuan.
“CGRP inhibited macrophage activity, and clusters of immune cells called tertiary lymphoid structures, needed to coordinate an effective response, failed to form.”
“It’s fascinating to observe how sensitive the immune response is to changes in its local environment,” he adds. “We’ve shown that increased neuronal activity is enough to reorganise the immune landscape of the tumour. It’s not just about the presence or absence of immune cells, it’s also how they respond to their surroundings.”
When the researchers disrupted local sensory nerve activity, or directly blocked CGRP signalling, this organisation was restored. B- and T-cell responses strengthened, and tumour growth was reduced.
Multiplex immunofluorescence staining of a human tertiary lymphoid structure.
Because smoking is the biggest risk factor for developing lung cancer, the team also asked whether cigarette smoke affects this neuroimmune interaction. In further experiments, they showed that cigarette smoke extract increases neuronal activity and accelerates tumour progression.
This reveals a mechanism by which smoking can promote cancer progression beyond its role in causing DNA damage.
Because drugs that target CGRP signalling are already used in other conditions, the researchers suggest this pathway could be explored as a way of improving the effectiveness of cancer immunotherapy.
“Even with the amazing progress we’ve seen in people benefitting from immunotherapy, a large proportion of lung cancers don’t respond,” says Giacomo. “This unique insight into tumour biology could offer a completely new way to improve those responses.”
“We’ve shown that nerves are not just present in cancers but actively shaping the tumour microenvironment and how cells talk to one another,” adds Leanne. “This opens a new direction for cancer research and future treatment, bringing neuroscience and immunology together.”
This work forms part of InteroCANCEption, a Cancer Grand Challenges team led by Leanne Li and funded by Cancer Research UK and the National Cancer Institute.
By investigating how the nervous system detects and influences tumour development, the team is working to understand how signals are exchanged across the tumour environment and how those signals might be redirected in future treatments.
Dr David Scott, Director of Cancer Grand Challenges, said “Understanding how the brain might detect tumours and even influence how they grow is an emerging frontier in cancer research. This is why Cancer Grand Challenges is enabling team InteroCANCEption, led by Leanne Li, to explore this bi-directional tumour-nervous system connection and potentially develop innovative approaches that target the nervous system, expanding what is possible in cancer treatment.”
