Abstract
Malignant melanoma is the deadliest cutaneous malignancy. Its prevalence is currently rising and accounts for 75% of skin cancer-related deaths in the United States. This prototypical immunogenic malignancy requires interaction with the immune system for progression. Investigation into the immunobiology of melanoma holds downstream potential for therapeutic targets and prognostic markers. Vitamin D is an immunomodulatory hormone that demonstrates anti-tumoral effects. The triggering receptor expressed on myeloid cells-1 (TREM-1) has been characterized as pro-tumoral and plays a large role cancer progression in numerous non- melanocytic malignancies. In the present study, the interaction of vitamin D and TREMs are explored in melanoma. Immunohistochemical evaluation of TREM-1 and TREM-2 levels in cutaneous melanoma tissue demonstrates the ratio to be a possibly important contributor in malignant state. Furthermore, TREM-1 levels were found to positively correlate with VDR levels in melanoma tissue. VDR, in turn, is inversely associated with melanoma tumor staging. In vitro evaluation of melanoma cells demonstrates vitamin D to induce TREM-1 expression, while having no effect on levels of TREM-2 and high mobility group box 1 (HMGB1), a TREM-1 ligand. Vitamin D also inhibits migration and invasion ability of treated cells, further supporting the anti-tumoral effects of vitamin D. Considering their vast respective immune functions, this complex interaction between vitamin D and TREM also holds broader implications cutaneous disorders. Characterization of cutaneous TREM levels demonstrates TREM-1 to be elevated in keratinocytes of vitamin D-sufficient swine, when compared to that of vitamin D-deficient skin. Levels of HMGB1 and another of its receptors, the receptor for advanced glycation endproducts, were not affected by vitamin D state. Rather, these two molecules demonstrated differences in expression based on cutaneous depth (i.e. basal cells versus upper keratinocytes), suggesting a role of this and the TREM pathways in keratinocyte differentiation and development. These immunomodulatory molecules hold large potential for clinical application. The value of vitamin D supplementation should be explored in high-powered randomized, controlled trials to determine its role in melanoma prevention and possibly adjuvant therapy. Modulation of TREM signaling, most notably TREM-1 inhibition, warrants further exploration in melanoma therapy. Furthermore, HMGB1 holds clinical value as a prognostic marker in numerous inflammatory and neoplastic conditions, including melanoma and non-melanocytic cutaneous malignancy. Melanoma is a complex immunogenic neoplasm that is not fully understood. Further effort in unraveling its multifaceted immunologic interplay will provide better understanding of this condition and generate novel targets for selective therapy.