DISSECTING THE ROLE OF THE IMMUNE MICROENVIRONMENT IN MELANOMA BONE METASTASIS

ABSTRACT Bone metastasis is a devastating consequence of cancer progression. In melanoma, almost 45% of metastatic patients will develop bone metastasis, with bone being the fourth most common site of metastasis after brain, liver, and lung. Once melanoma cells infiltrate the skeleton, the increased risk of skeletal related events— including bone fractures and pain—profoundly reduces quality of life. Melanoma patients who present with bone metastases have poorer responses to immune checkpoint blockade than patients who develop metastases in visceral organs or the brain. Evidence from multiple myeloma and both breast and prostate adenocarcinomas suggest the bone microenvironment (BMM) plays an important role in metastatic colonization. However, we know little about the mechanisms melanoma cells use to infiltrate and modify the skeleton, communicate with immune cells, and resist immunotherapy. This is in part due to the scarcity of preclinical models that truly recapitulate human melanoma bone metastasis. We have established preclinical murine models that recapitulate human melanoma bone metastasis. We will compare bones from these models to naïve, non-tumor bearing bone to define the mechanisms melanoma cells use to colonize the skeleton and modify the BMM. In these models, we have observed a higher number of reactive neutrophils (bone metastasis-associated neutrophils or BMANs), which express an IFNg-response signature characterized by high expression of a family of protease inhibitors called Stefins. Our proposed functional studies will reveal whether BMANs support melanoma cell adaptation to the bone parenchyma. Additional single-cell analyses, using both murine models and patient samples, will uncover at high resolution the interplay between tumor, skeletal, and immune cells during melanoma bone metastasis. The successful outcomes from this work will improve our understanding of how melanoma grows in bone and pave the way for better treatments for bone disease.