Melanoma is one of the most aggressive forms of skin cancer, with a strong tendency to spread beyond the primary tumour. For many patients, the first destination is the lymphatic system, where melanoma cells establish themselves within nearby lymph nodes. Once melanoma reaches the lymph nodes, the risk of recurrence and progression increases significantly.
In a research project funded by AMRF in 2022, Dr Isobel Leece at Monash University explored what happens when melanoma enters the lymph nodes, uncovering important insights into how cancer interacts with the immune system and identifying new tools that could help accelerate future melanoma research.
Lymph nodes play a critical role in the body’s immune defence. They act as hubs where immune cells communicate, recognise threats and coordinate responses against infections and cancer.
In theory, lymph nodes should be hostile environments for melanoma cells. However, melanoma frequently establishes metastases within these structures and can continue to spread throughout the body.
To better understand this interaction, Dr Leece examined lymph node samples from 44 melanoma patients using advanced imaging techniques capable of identifying and mapping multiple immune cell types within a single tissue sample.
This grant has provided a solid foundational understanding of immunity within melanoma-invaded lymph nodes and allowed us to validate a new model. We are hopeful that this work will continue to help answer the questions of how melanoma metastasises. It has been a real honour to work on this project and AMRF funding has really opened doors for me. – Dr Isobel Leece
The findings revealed that many of the immune cells responsible for attacking cancer were largely excluded from melanoma deposits within the lymph nodes. While some immune activity remained, the overall picture suggested that melanoma is able to create an environment that limits effective immune surveillance and tumour destruction. Factors such as tumour heterogeneity, the genetic diversity within cancer cells, were strongly associated with how melanoma behaved and spread.
Further, the study identified differences in immune cell populations that were associated with patient outcomes. Patients with increased Natural Killer T (NKT) cell infiltration tended to experience better outcomes, while higher levels of B cells were associated with poorer overall survival. Roughly a quarter of patients did have multiple types of cytotoxic cells, both CD8 T cells and Natural Killer cells (NK), infiltrate into the tumour. However, they were unable to completely prevent metastasis, highlighting the challenges faced by the immune system once melanoma becomes established within the lymphatic environment.
Improving Laboratory Models for Metastatic Melanoma
A major component of the project involved developing new laboratory models that more accurately mimic the way melanoma spreads to lymph nodes.
The research team generated two novel melanoma cell lines from genetically engineered mouse tumours. One of these models was exposed to ultraviolet (UV) radiation to recreate the DNA damage commonly seen in human melanoma.
The UV-exposed melanoma accumulated large numbers of mutations and developed greater genetic diversity, closely resembling the complex biology observed in patient tumours.
These new models successfully formed tumours in the skin, spread to regional lymph nodes, and triggered immune responses in mice, creating a powerful platform for studying melanoma metastasis in real time. These models also saw increases in CD8 T cells and NK cells in the lymph nodes, recapitulating what was seen in the patient lymph nodes.
While this research is primarily focused on understanding the biology of melanoma metastasis, its findings have important implications for future patient care.
By improving our understanding of the complex relationship between melanoma and the immune system within lymph nodes, this research contributes valuable knowledge that could inform the next generation of therapies. And the development of new melanoma models that accurately mimic lymph node metastasis provides researchers with valuable tools for testing future therapies.
The Australian Melanoma Research Foundation is proud to support emerging researchers whose work is helping to unlock new answers and bring us closer to better outcomes for people affected by melanoma.
