Cutaneous melanoma is one of the most common cancers in people with fair skin. While melanoma is often diagnosed at an early stage, with the potential for curative-intend surgery to the primary site, in some patients spread of tumour cells to the sentinel lymph nodes (SLN) will have already occurred. Patients with microscopic cancer deposits in SLN have a higher risk of melanoma re-occurrence and cancer-specific mortality. However, the majority of patients will not relapse, which may indicate immune-mediated tumour cell control.
We have recently developed a murine model of cutaneous melanoma, that not only shows tumour formation with variable growth kinetics and penetrance but also spontaneously metastasises to draining lymph nodes, resembling melanoma in humans. In order to better understand the mechanisms underlying metastasis development and immune control, we surgically excised primary tumours in mice, modelling curative-intend surgery in patients. We found that mice genetically deficient for perforin developed lymph node metastases with higher incidence and faster progression compared to wildtype animals, indicating a role for this soluble mediator in control of metastases. Furthermore, mice depleted of NK cells showed a profound defect in control of metastatic dissemination. Interestingly, some mice developed macroscopic metastases several weeks after surgery, suggesting that in these mice, micro-metastatic deposits had been controlled over extended periods of time. Finally, in some mice metastases were not confined to draining lymph nodes but also spread to visceral organs. These results highlight the broad spectrum of disease outcomes in mice after epicutaneous inoculation, ranging from immune control to metastatic disease, similar to what has been observed in patients.
Our novel melanoma and surgery model sets the stage for investigating the molecular mechanisms and identifying critical mediators in metastasis control, with the ultimate goal of refining SLN assessment and preventing immune escape in the clinic.