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Legends for Supplementary Figures S1-S19.

Supplementary Fig. S17. Representative immunohistochemistry showing intratumoral, peritumoral, and marginal tissue stained for IL-18 from patients.

Supplementary Figures S1-S16, S18, and S19 and Supplementary Tables S1-S4. Supplementary Fig. S1. Stratification of patients based on IL-18 staining density in intratumoral and peritumoral tissue. Supplementary Fig. S2. Efficient fibrosis induction by carbon tetrachloride and slightly modulated fibrosis burden between WT and IL18R1-/- mice. Supplementary Fig. S3. Multiple cell types produce IL-18 and IL18R1 in HCC. Supplementary Fig. S4. Enhanced neutrophil-to-lymphocyte ratios and decreased circulating lymphocytes in tumor-bearing IL18R1-/- mice. Supplementary Fig. S5. NK and NKT cells in liver and tumor are not significantly different between WT and IL18R1-/- mice. Supplementary Fig. S6. Myeloid cell accumulation in liver and tumor are not significantly different between WT and IL18R1-/- mice. Supplementary Fig. S7. Quantification of NK and T-cell populations in WT and IL18R1-/- mice. Supplementary Fig. S8. Representative flow cytometry of T-cell populations in non-tumor liver, tumor, and spleen in WT and IL18R1-/- mice. Supplementary Fig. S9. Alternative tumor models yield similar skewing of T-cell populations in the tumor by loss of IL18R1. Supplementary Fig. S10. Slightly increased proportions of CD44+ T-cells in IL18R1-/- mice compared to WT. Supplementary Fig. S11. No significant changes in CD4+ CD25+ cells, CD4+ FoxP3+ cells, or CD4+ CD25+ FoxP3+ cells. Supplementary Fig. S12. Modestly decreased PD-1 in CD8+ T cells in IL18R1-/- mice compared with WT mice. Supplementary Fig. S13. Slight differences in cytokine production, no differences in granzyme production in T-cells between WT and IL18R1-/- mice. Supplementary Fig. S14. Representative flow cytometry of differentiation and cytokine production of CD4+ T-cells from WT and IL18R1-/- mice. Supplementary Fig. S15. Representative flow cytometry of WT and IL18R1-/- CD8+ T-cell survival and proliferation upon reactivation and stimulation. Supplementary Fig. S16. Tumor-infiltrating NK cells have altered cytokine and transcription factor production between WT and IL18R1-/- mice. Supplementary Supplementary Fig. S18. Differences in IL-18 staining density between intratumoral and peritumoral tissue are more closely linked to peritumoral staining density. Supplementary Fig. S19. No difference in survival based on expression of IL18R1 in patient samples. Supplementary Table S1. Antibodies, Dyes, Stains, and Recombinant Proteins Used. Supplementary Table S2. qPCR Primers and shRNAs Used. Supplementary Table S3. Correlations between Patient Characteristics and Phenotypes and IL-18 Staining Density in Our 138 Patient Cohort. Supplementary Table S4. Average Density of Intratumoral and Peritumoral IL-18 Staining in Our 138 Patient Cohort.

Chronic inflammation in liver tissue is an underlying cause of hepatocellular carcinoma. High levels of inflammatory cytokine IL18 in the circulation of patients with hepatocellular carcinoma correlates with poor prognosis. However, conflicting results have been reported for IL18 in hepatocellular carcinoma development and progression. In this study, we used tissue specimens from hepatocellular carcinoma patients and clinically relevant mouse models of hepatocellular carcinoma to evaluate IL18 expression and function. In a mouse model of liver fibrosis that recapitulates a tumor-promoting microenvironment, global deletion of the IL18 receptor IL18R1 enhanced tumor growth and burden. Similarly, in a carcinogen-induced model of liver tumorigenesis, IL18R1 deletion increased tumor burden. Mechanistically, we found that IL18 exerted inflammation-dependent tumor-suppressive effects largely by promoting the differentiation, activity, and survival of tumor-infiltrating T cells. Finally, differences in the expression of IL18 in tumor tissue versus nontumor tissue were more predictive of patient outcome than overall tissue expression. Taken together, our findings resolve a long-standing contradiction regarding a tumor-suppressive role for IL18 in established hepatocellular carcinoma and provide a mechanistic explanation for the complex relationship between its expression pattern and hepatocellular carcinoma prognosis. Cancer Res; 76(8); 2394–405. ©2016 AACR.

More detailed descriptions of patients and experimental protocols.

OBJECTIVES Patients with advanced ampullary carcinoma (AC) who are unsuitable for surgery are most likely to have poor outcomes. The role of endoscopic radiofrequency ablation (RFA) in this population has not been fully defined. We aimed to assess the short- and long-term outcomes of RFA in a large cohort of AC patients. METHODS In this retrospective study, data of consecutive patients with pathologically proven AC who underwent successful endobiliary RFA and/or stent placement were collected. All patients did not undergo surgical resection. The primary outcome was overall survival (OS). The secondary outcomes included clinical success and adverse events. RESULTS A total of 85 patients, 50 in the RFA plus stenting group and 35 in the stenting alone group, were identified. The median OS was significantly longer in the RFA group than in the stenting alone group (16.9 vs. 9.8 months, P