Inflammation induces GILT expression in human melanoma

Abstract

Abstract T cell-mediated immunity can produce durable anti-melanoma responses resulting in improved survival of metastatic melanoma patients. Gamma-interferon-inducible lysosomal thiol reductase (GILT) is critical for MHC class II-restricted presentation of multiple melanoma antigens to CD4+ T cells and facilitates cross-presentation on MHC class I for activation of CD8+ T cells. Our prior study found that GILT expression is increased in melanocytes of malignant melanoma specimens compared with benign nevi. To determine whether GILT expression is associated with inflammation, expression in halo nevi specimens was compared to nevi without lymphocytic infiltrate by immunohistochemistry. A halo nevus is a benign nevus with a lymphocytic infiltrate which leads to regression of the nevus. GILT, but not MHC class II, expression was increased in melanocytes of halo nevi compared to nevi without lymphocytic infiltrate. Analysis of a publicly available gene expression profiling cohort of 457 cutaneous melanoma specimens revealed that GILT expression was associated with IFN-γ, TNF-α, and IL-1β expression in human melanoma. In vitro exposure of human melanoma cell lines to IFN-γ or inflammatory cytokines, such as TNF-α, induced GILT expression in melanoma cell lines, which lacked GILT expression at baseline. Vemurafenib, a BRAF inhibitor used in the treatment of metastatic melanoma, enhanced IFN-γ-induced GILT and MHC class II expression in a melanoma cell line. Together these data demonstrate that inflammation, alone or in combination with a current therapeutic agent, induces high levels of GILT expression in human melanoma.