Most patients diagnosed with cutaneous melanoma have early stage disease, 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 and these patients have a worse prognosis. However, the majority of patients with microscopic deposits in SLNs 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 mechanisms underlying metastasis development and immune control, we surgically excised primary tumours, 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 metastasis control. Furthermore, mice depleted of NK cells showed a profound defect in control of metastatic dissemination. Interestingly, some mice developed metastases several weeks after surgery, suggesting that micro-metastatic deposits may have been controlled over extended periods of time. Finally, some mice developed metastases in visceral organs as well as in draining lymph nodes. These results highlight the broad spectrum of outcomes in mice after epicutaneous inoculation, from immune control to metastatic disease, similar to patterns observed in patients.
Our novel melanoma and surgery model sets the stage for investigating molecular mechanisms and identifying critical mediators in metastasis control, with the goal of refining SLN assessment and preventing immune escape in the clinic.