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Background Patients with ankylosing spondylitis (AS) have significantly lower quality of life (QoL) than the general population. Holistic interventions addressing QoL include spa- or balneotherapy. Inclusion of radon in spa-therapy treatments is beneficial in reducing pain and shows promising results in improving QoL in AS-patients. We aimed to explore the association of spa therapy including low-dose radon with systematically monitored QoL in AS-patients over an extended timeperiod.MethodsRegistry data collected for the “Radon indication registry for the assessment of pain reduction, increase of quality of life and improvement in body functionality throughout low-dose radon hyperthermia therapy” in the Austrian Gastein valley comprising data on QoL (EuroQol EQ-5D) directly before the treatment (baseline), directly, 3; 6 and 9 months after the treatment, age, sex and body mass index (BMI) were analysed. Two linear regression models explored the association between time of measurement with 1) EQ-5D utilities and 2) EuroQol visual analogue scale (VAS) score. Alterations of 0.05 (utilities) and 5.00 (VAS) were considered clinically relevant.ResultsTwo-hundred-ninety-one AS-patients were included in the analyses. Forty-four percent (n=128) were women, the mean age was 52 (SD 10) and the average BMI was 26 (SD 4). Utilities and VAS were significantly higher at all timepoints compared to baseline. Improvements were clinically relevant at all timepoints in case of the EQ-5D VAS and until 6 months after treatment for the utility index.ConclusionSpa therapy including radon results in significant and clinically relevant improvements in Qol of AS-patients until 6-9 months after treatment.

Pharmacological targeting of Hedgehog (HH)/GLI has proven effective for certain blood, brain and skin cancers including basal cell carcinoma (BCC). However, limited response rates and the development of drug resistance call for improved anti-HH therapies that take into account synergistic crosstalk mechanisms and immune evasion strategies.In previous work, we demonstrated that crosstalk of HH/GLI with pro-inflammatory Interleukin-6 (IL6) signaling drives BCC by promoting tumor cell proliferation [1]. In the present study, we screened for possible mechanisms of cancer immune evasion regulated by synergistic HH-IL6 signaling and identified the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1) as a novel transcriptional target co-regulated by HH-IL6 signaling. Analysis of thecis-regulatory region of IDO1 by chromatin-immunoprecipitation revealed co-occupancy of this region by HH- IL6 induced GLI1 and STAT3 transcription factors along with active chromatin marks at the histone level. Elevated expression of IDO1 in human BCC with high-level HH and IL6 signatures supports the clinical relevance of our mechanistic data. Genetic inhibition of GLI1 expression prevented the induction of IDO1 expression in response to IL6/STAT3 and IFNγ/STAT1 signaling in human melanoma cells. Pharmacological targeting of HH signaling at the level of GLI proteins interfered with IDO1 expression and consequently prevented the production of the immunosuppressive metabolite kynurenine generated by active IDO1 from tryptophan. Further, inhibition of GLI1 enhanced the efficacy of the selective IDO1 inhibitor epacadostat. Of note, inhibition of HH/GLI signaling in melanoma cells not only reduced IDO1 expression but also interfered with the repression of T cell activation by attenuating IDO1/kynurenine-mediated immunosuppression. These data identify the immunosuppressive IDO1-kynurenine pathway as a novel pro-tumorigenic effector of oncogenic HH-IL6 and GLI-STAT cooperation. Our data suggest simultaneous pharmacological targeting of the HH/GLI, JAK/STAT and IDO1- kynurenine axis as rational combination therapy in skin cancers.