Interferon- 2; signaling in melanocytes and melanoma cells regulates expression of CTLA-4

CTLA-4 is a cell surface receptor on T cells that functions as an immune checkpoint molecule to enforce tolerance to cognate antigens. Anti-CTLA-4 immunotherapy is highly effective at reactivating T cell responses against melanoma, which is postulated to be due to targeting CTLA-4 on T cells. Here we report that CTLA-4 is also highly expressed by most human melanoma cell lines, as well as in normal human melanocytes. Interferon-gamma (IFNG) signaling activated the expression of the human CTLA-4 gene in a melanocyte and melanoma cell-specific manner. Mechanistically, IFNG activated CTLA-4 expression through JAK1/2-dependent phosphorylation of STAT1, which bound a specific gamma-activated sequence (GAS) site on the CTLA-4 promoter, thereby licensing CBP/p300-mediated histone acetylation and local chromatin opening. In melanoma cell lines, elevated baseline expression relied upon constitutive activation of the MAPK pathway. Notably, RNA-seq analyses of melanoma specimens obtained from patients who had received anti-CTLA-4 immunotherapy (ipilimumab) showed upregulation of an IFNG-response gene expression signature, including CTLA-4 itself, which correlated significantly with durable response. Taken together, our results raise the possibility that CTLA-4 targeting on melanoma cells may contribute to the clinical immunobiology of anti-CTLA-4 responses.

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