Abstract

Background: IFN-γ is widely debated regarding its purported anti- or pro-tumorigenic properties. We initiated a pilot study of primary malignant melanoma patients to investigate whether macrophage-derived IFN-γ is produced in humans as proposed in murine melanomagenesis models. Methods: Biopsy specimens of fresh-frozen primary melanoma tissue were used to quantify co-localization of IFN-γ, macrophages, lymphocytes, and downstream IFN-γ signatures. Additionally, we analyzed simulated solar radiation (SSR) exposed skin in patients with a history of melanoma versus healthy controls to compare the relative magnitude of macrophage infiltration. Results: Our data identified a subset of tumor infiltrating CD68+ macrophages that co-localized with IFN-γ (Pearson’s Correlation = 0.33 ± 0.11) in patients with primary melanoma (Stage 0-III). Additionally, a population of infiltrating CD3+ lymphocytes strongly co-localized with IFN-γ (Pearson’s Correlation = 0.57 ± 0.11). Malignant melanoma cells were double positive for downstream IFN-γ response elements, MIG/CXCL9, and phosphorylated STAT-1 (P-STAT-1). Cellular signaling pathways were also observed when we exposed the skin of melanoma patients to SSR. Despite robust CXCL9 expression in the epidermis of SSR-exposed skin of melanoma patients, we observed decreased macrophage infiltration into melanoma patient skin. Conclusion: Peritumoral macrophages in melanoma patient skin produce IFN-γ and melanocytes appear to exhibit in vivo responsiveness to IFN-γ, such as P-STAT-1 and upregulated CXCL9 expression. However, despite producing CXCL9 in response to SSR, the normal skin of melanoma patients demonstrates a weak leukocyte infiltration. Immune-modulatory studies for the prevention or treatment of human malignant melanoma may need to address complex tissue and melanocyte signaling and crosstalk.