Phototherapy-induced interferon kappa drives type I interferon mediated anticancer responses in cutaneous T cell lymphoma

Phototherapy is a T cell immunosuppressive therapy that effectively treats inflammatory skin diseases and improves cutaneous T cell lymphoma by unclear mechanisms. We observed defective type I interferon production in untreated CTCL skin lesions. Effective tumor clearance was associated with upregulation of type I interferon production, increased recruitment of CD8 T cells into tumors and gene expression changes characteristic of antigen specific T cell activation. Malignant T cell numbers in skin were associated with increased expression of IRF2, a negative regulator of interferon production. Phototherapy increased gene and protein expression of interferon kappa, a UVB inducible up-regulator of type I interferon production. In vitro, UVA exposure induced production of interferon kappa by human keratinocytes that preceded upregulation of other type I interferons. Keratinocytes deficient in interferon kappa had decreased baseline and induced type I interferon expression in response to UVA. In summary, we find that phototherapy up regulates keratinocyte interferon kappa production, leading to enhanced type I interferon production and improved anticancer responses. These studies demonstrate a baseline deficit in type I interferon production in CTCL and suggest a role for interferon kappa in the mechanism of action of phototherapy.