Pancreatic cancer is characterized by a microenvironment suppressing immune responses. RIG-I-like helicases (RLH) are immunoreceptors for viral RNA that induce an antiviral response program via the production of type I interferons (IFN) and apoptosis in susceptible cells. We recently identified RLH as therapeutic targets of pancreatic cancer for counteracting immunosuppressive mechanisms and apoptosis induction. Here, we investigated immunogenic consequences of RLH-induced tumor cell death. Treatment of murine pancreatic cancer cell lines with RLH ligands induced production of type I IFN and proinflammatory cytokines. In addition, tumor cells died via intrinsic apoptosis and displayed features of immunogenic cell death, such as release of HMGB1 and translocation of calreticulin to the outer cell membrane. RLH-activated tumor cells led to activation of dendritic cells (DCs), which was mediated by tumor-derived type I IFN, whereas TLR, RAGE or inflammasome signaling was dispensable. Importantly, CD8aþ DCs effectively engulfed apoptotic tumor material and cross-presented tumorassociated antigen to naive CD8 þ T cells. In comparison, tumor cell death mediated by oxaliplatin, staurosporine or mechanical disruption failed to induce DC activation and antigen presentation. Tumor cells treated with sublethal doses of RLH ligands upregulated Fas and MHC-I expression and were effectively sensitized towards Fas-mediated apoptosis and cytotoxic T lymphocyte (CTL)-mediated lysis. Vaccination of mice with RLH-activated tumor cells induced protective antitumor immunity in vivo. In addition, MDA5-based immunotherapy led to effective tumor control of established pancreatic tumors. In summary, RLH ligands induce a highly immunogenic form of tumor cell death linking innate and adaptive immunity.

The RIG-I-like helicase melanoma differentiation-associated protein 5 (MDA5) is an innate immune receptor for double-stranded viral RNA (dsRNA) that, upon activation, induces a Type I interferon (IFN)-driven immune response. In the present study, we demonstrate that human und murine pancreatic cancer cells express functional MDA5 and are highly sensitive to MDA5-induced cell death. Activation of MDA5 by cytosolic delivery of the synthetic dsRNA analog poly(I:C) led to phosphorylation of the transcription factor IRF3, IFNβ production and upregulation of MHC-I expression. MDA5 signaling also induced tumor cell apoptosis via the intrinsic pathway and sensitized tumor cells toward extrinsic, Fas-mediated apoptosis. Systemic treatment of orthotopic pancreatic cancer-bearing mice with the MDA5 ligand resulted in activated CD8+ T cell tumor infiltration, an increased frequency of tumor antigen-specific CD8+ T cells and an immunogenic cytokine milieu in the tumor microenvironment. These effects were paralleled by MDA5-induced pronounced tumor cell death in situ and significantly prolonged survival in two different mouse models for pancreatic cancer, an immunotherapeutic response dependent on CD8+ T cells. Treated mice were further protected from subsequent tumor challenge. In summary, we identified MDA5 as a novel therapeutic target for overcoming apoptosis resistance and tumor-mediated immunosuppression in pancreatic cancer. MDA5 ligands link innate with adaptive immune mechanisms for effective tumor control.

<b><i>Introduction:</i></b> Selective internal radiation therapy (SIRT) is a local treatment option for patients with hepatocellular carcinoma (HCC). Its exact role next to other HCC therapies has yet to be defined. In order to identify patients most suitable for SIRT, a SIRT-specific prognostic score should be developed. <b><i>Methods:</i></b> A cohort of 72 SIRT patients treated at the University Hospital of Munich was retrospectively analyzed. The prognostic performance of 12 HCC staging systems and prognostic scores was assessed. Cox-regression analysis was used to identify independent prognostic factors, which formed the basis of the Munich-SIRT score (M-SIRT). All scores were ranked by calculating the c-Index and Akaike information criterion (AIC). External validation was performed in a cohort of 128 SIRT patients treated at the University Hospital of Pamplona, Spain. <b><i>Results:</i></b> median overall survival was 13 months (95% confidence interval 9.9–21.9). AFP (<i>p</i> = 0.005; hazard ratio [HR] 2.38), albumin (<i>p</i> &#x3c; 0.001; HR 5.87), and alkaline phosphatase (<i>p</i> &#x3c; 0.001; HR 8.38) were identified as independent prognostic factors. M-SIRT comprises 3 prognostic groups with a median survival of 38.9, 14.6, and 7.7 months, respectively (I vs. II: <i>p</i> = 0.003, II vs. III: <i>p</i> &#x3c; 0.001). AIC (318) and concordance index (0.711) ranked M-SIRT superior to the established HCC staging systems, and the score successfully passed external validation in an independent SIRT cohort (I vs. II: <i>p</i> = 0.03; II vs. III: <i>p</i> = 0.007). <b><i>Conclusion:</i></b> Therapy-specific prognostic scores can facilitate treatment decisions and prognostication for HCC patients. Considering its performance in 200 SIRT patients, M-SIRT is a promising prognostic tool for HCC patients evaluated for SIRT.

Background/Aims: The recently proposed Munich-transarterial chemoembolisation-score (M-TACE) was tailored to suit hepatocellular Carcinoma (HCC) patients evaluated for TACE. M-TACE outperformed the established HCC-staging-systems and successfully passed external validation. Modifications of staging-systems through the rearrangement of stages or by adding prognostic factors are methods of improving prognostic power. M-TACEs performance compared to scores modified this way should be tested. Methods: Seven well-known HCC staging-systems (including Cancer of the Liver Italian Program-score [CLIP] and Barcelona Clinic liver cancer [BCLC]) and 2 TACE-specific scores (Selection for Transarterial Chemoembolisation Treatment [STATE] and Hepatoma Arterial embolisation Prognostic [HAP]) were rearranged in a cohort of 186 TACE-patients through score-point-analysis and subsequent linking of non-significant adjacent score-points. Additionally, a new score was constructed by combining the top established staging-system in TACE patients (CLIP-TACE) and the prognostic parameter with the highest hazard ratio for death in the TACE-cohort [C-reactive protein (CRP)]. Additionally, the TACE-tailored-scores were applied to an external TACE-cohort (n = 71). ­Results: Rearrangement resulted in optimal stratification and monotonicity. CLIP-TACE demonstrated the best prognostic capability of all rearranged scores (c-index 0.668, AIC 1294) and the addition of CRP yielded further prognostic improvement (c-index 0.680, AIC 1289). However, superiority over M-TACE could not be achieved by any of the new scores in the internal and external cohort. Conclusion: M-TACE outperforms TACE-tailored modifications of all relevant HCC-staging-systems. Prospective validation of M-TACE to promote its role as the preferred staging-system for TACE-patients is therefore justified.

Background and Aim: This retrospective, multicenter study aims to assess the efficacy and safety in Wilson disease (WD) patients treated with trientine tetrahydrochloride (TETA 4HCl) after switch from trientine dihydrochloride (TETA 2HCl). Methods: In total, 68 WD patients with stable copper metabolism were identified to receive TETA 4HCl (Cuprior ™ ) after previous treatment with TETA 2HCl. We analyzed biochemical markers such as urinary copper, serum copper, non-coeruloplasmin bound copper (NCC), and transaminases as well as clinical scores (APRI; FIB-4 score) at baseline with a follow-up (FU) of 12 months. Safety of TETA 4HCl treatment was based on reported adverse events (AEs). Results:The study cohort reflects a common WD cohort with a mean age of 20.3 years at diagnosis and 38.3 years at baseline. There are no significant differences concerning serum copper, NCC, transaminases, APRI, and FIB-4 score in the 3-month FU. Six-month FU revealed a decreased AST (P = 0.008), APRI (P = 0.042), and FIB-4 score (P = 0.039). GGT varied only borderline significantly in the 3-month, but not in the 6-month FU. Comparison of urinary copper within the subsets did not reveal a difference to baseline in all FUs, suggesting stable control of copper metabolism. Few AEs during TETA 4HCl treatment were reported, most commonly gastrointestinal discomfort. Only three treatments with TETA 4HCl were discontinued. Conclusion:Copper parameters and liver function were stable after treatment switch to TETA 4HCl. Treatment with TETA 4HCl was generally well tolerated. This study indicates that the switch from TETA 2HCl to TETA 4HCl is safe and viable.Falk. U Merle received travel grants from Gilead and Falk. G Denk received honoraria for teaching from AbbVie, Falk Foundation, Gilead, Intercept, Novartis and Orphalan. G Denk received travel grants from AbbVie, Gilead and Intercept. Aurélia Poujois advises for Alexion, Orphalan, Ultragenyx, Univar, Vivet therapeutics. Aurélia Poujois received research funding (to the institution) from AddMedica, Orphalan, and Merz. KH Weiss advises for Alexion, Bayer, Chiesi, Eisai, Orphalan, Pfizer, Ultragenyx, Univar, Vivet therapeutics. KH Weiss received research funding (to the institution) from Alexion, Novartis, Orphalan, Univar. KH Weiss received travel grants from Abbvie, Bayer and Gilead.Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional ethical committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The study was a priori approved by the local ethics committee.Informed consent: All patients provided informed consent for the analysis of their chart data. Informed consent for the procedure and management was obtained from all individual participants included in the study.