605 Phototherapy-induced IFNκ drives type I IFN induced anticancer responses in CTCL

Abstract

Study of Stage I-II mycosis fungoides (MF) skin lesions from 14 patients by gene expression profiling demonstrated reduced expression of six type I IFNs compared to healthy human skin. Psoralen plus UVA therapy (PUVA) induced increased levels of type I IFNs that were associated with CD8 T cell recruitment into tumors, expression of antigen specific T cell activation genes and depletion of malignant T cells. MF skin lesions expressed significantly higher levels of two negative regulators of IFN production, IRF2 and IFI35; IRF2 levels correlated with the number of malignant T cells in skin. IRF2 is known to antagonize epithelial production of type I IFNs. Indeed, we found reduced expression of ULBP2, a marker of epithelial type I interferon production. Immunostaining confirmed reduced epidermal production of type I alpha IFNs that was reversed by PUVA therapy. IFNκ is an epithelial type I interferon induced by UVB that triggers production of other type I IFNs and is responsible for the flaring of cutaneous lupus after sun exposure. We studied human keratinocytes treated with UVA with or without psoralen. IFNκ enhanced keratinocyte production of type I IFNs and downstream interferon genes in response to UVA. IFNκ knockout keratinocytes had markedly reduced type I IFNs induction after UVA, illustrating the key role of epithelial IFNκ in boosting type I interferon production. In summary, we find that type I IFNs are markedly reduced in MF lesions, that phototherapy induces epithelial type I interferon production via INFκ and that this increase is associated with effective tumor clearance. Our results suggest other medications that induce epithelial type I IFNs, including MEK or EGFR inhibitors, may be effective therapies for CTCL.