Uracil-DNA glycosylase deficiency is associated with repressed tumor cell-intrinsic inflammatory signaling and altered sensitivity to exogenous interferons

Abstract

2-deoxyuridine (dU) is a common DNA lesion resulting from cytosine deamination and from dUMP incorporation by DNA polymerases, both of which are prevalent in cancer. The primary mechanism that repairs dU lesions in genomic DNA is base excision repair initiated by Uracil-DNA Glycosylase 1 (UNG1). We generated Ung knockout mouse B16 melanoma cells to investigate the consequences of UNG deficiency in a well-characterized, immunoproficient, syngeneic mouse cancer model. We show that UNG-deficient ({Delta}UNG) B16 tumors have altered growth kinetics in vivo and that their delayed growth is T-cell dependent. Immune profiling revealed reduced CD8+ T cell infiltration but augmented CD4+ Th1 responses in {Delta}UNG tumors. In vitro, {Delta}UNG tumor cells exhibit strongly suppressed cell-intrinsic type-I interferon, type-II interferon, and inflammatory signaling gene expression signatures as well as altered cytokine and chemokine secretion. In vivo, {Delta}UNG tumors exhibit a modified inflammatory cytokine and chemokine milieu. Furthermore, {Delta}UNG tumor cells have altered sensitivity to exogenous interferons in vitro, with increased sensitivity to IFN-{gamma} but decreased sensitivity to IFN-/{beta}. Collectively, our data show that tumor cell-specific UNG deficiency results in an altered tumor microenvironment in vivo and provide proof-of-concept data for the use of UNG inhibitors to modulate inflammatory pathways in tumors.