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Mo X , Zhang H , Preston S , Martin K , Zhou B , Vadalia N , Gamero AM , Soboloff J , Tempera I , Zaidi MR
Interferon-gamma signaling in melanocytes and melanoma cells regulates expression of CTLA-4
Cancer Res. 2018 Jan 15;78(2) :436-450
PMID: 29150430    PMCID: PMC5771950    URL: https://www.ncbi.nlm.nih.gov/pubmed/29150430
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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.
1538-7445 Mo, Xuan Zhang, Hanghang Preston, Sarah Martin, Kayla Zhou, Bo Vadalia, Nish Gamero, Ana M Soboloff, Jonathan Tempera, Italo Zaidi, M Raza R01 CA193711/CA/NCI NIH HHS/United States Journal Article United States Cancer Res. 2017 Nov 17. pii: 0008-5472.CAN-17-1615. doi: 10.1158/0008-5472.CAN-17-1615.