Sometimes, the key to fighting a disease lies in discovering a single cell where it shouldn't be. Such an unexpected twist led to a breakthrough in our understanding of melanoma, revealing how our body’s own systems can inadvertently shield this deadly skin cancer.
Qi-Jing Li, a Distinguished Principal Scientist at A*STAR’s Institute of Molecular and Cell Biology (IMCB) and Singapore Immunology Network (SIgN), said: “Our collaborator, Tao Yin, made the crucial observation that many clinical melanoma samples showed an enrichment of nerves.” This suggested that something unusual was at play, involving nerve growth factor (NGF), a protein that promotes the growth of nerve cells.
Li, Yin and an international team of cancer researchers from the US and China, co-led by Xiao-Fan Wang, a Donald D. and Elizabeth G. Cooke Distinguished Professor of Cancer Research at Duke University, US, posited that NGF might also allow treatment-resistant melanomas to evade the immune system by blending seamlessly into the tumour microenvironment.
To prove their hypothesis, the team used CRISPR-Cas9 gene-editing tools to engineer NGF-deficient melanoma cells, which were then injected into mice. The results were promising: these modified cells grew more slowly and allowed more immune cells, such as CD8+ T cells, to penetrate the growing tumours, which significantly boosted the body’s ability to fight their formation.
Li and colleagues also found that even though some T cells might penetrate tumours in normal circumstances, NGF directly impeded their activation and function, especially when it came to T cell types crucial for long-term immune memory. To address this, the team repurposed a targeted cancer drug, named larotrectinib, which inhibits the interactions between NGF proteins and TrkA receptors found on melanoma cells.
Remarkably, this therapy not only helped to shrink existing tumours, but also prevented them from returning; it transformed 'cold' tumours, typically unresponsive to treatment, into 'hot' tumours that the immune system can attack. These findings indicate that TRK inhibitors like larotrectinib—already approved for various cancer types—can be a game-changer for patients with melanoma.
The researchers also identified a distinct genetic profile from NGF-deficient mouse tumours, and characterised the immune response within them. When tested against clinical data, the profile was a robust predictor of how well human patients would respond to immunotherapy.
“My lab had previously developed a popular algorithm to interpret tumour immunity across 280 dimensions.“ By focusing on the immunity-related features of NGF signalling as a refined biomarker, we were able to robustly predict patient outcomes even before the immunotherapy paradigm was established,” said Li, highlighting the power of mechanism-relevant biomarkers in therapeutic breakthroughs.
Moving forward, Li and colleagues are planning a clinical trial in collaboration with pharmaceutical partners. They aim to not only develop more effective treatments for melanoma, but to potentially unlock new treatment strategies for other cancers with similar evasion tactics.
The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB) and Singapore Immunology Network (SIgN).
