Delineating novel mechanism of immune evasion in melanoma brain metastases

Brain metastasis, the spread of cancer to the brain, is a leading cause of death in melanoma patients. Despite the application of multiple treatment modalities, melanoma brain metastasis (MBM) has an extremely grim prognosis with a median survival of only 4 months. Importantly, more and more melanoma patients are diagnosed and die from brain metastasis due to improved survival from newly developed treatments. We recently showed increased neurotrophin secretion by cancer cells and subsequent Trk pathway activation as a crucial resistance mechanism to treatment in several cancers including glioblastoma and melanoma. TrkA-C proteins are oncogenes that bind neurotrophins. Neurotrophins are growth factors and upon binding to Trk proteins, they promote cellular growth and survival. Our new findings suggest that melanoma cells that metastasize to the brain harbor higher Trk levels compared with cells that spread to other regions, potentially suggesting that melanoma cells with high Trk expression are primed for metastasis to the brain. We further found that MBM triggers less immune response vs. melanoma outside the brain. Therefore, we propose to study the role of the Trk pathway to promote brain metastasis and regulate immune evasion.