Local and systemic cytokine signatures for outcome prediction after transarterial chemoembolization in hepatocellular carcinoma

PURPOSE: Conventional transarterial chemoembolization (cTACE) is a guideline-approved therapy for unresectable hepatocellular carcinoma (HCC). This study aimed to characterize systemic and local cytokine changes induced by cTACE, and to evaluate their correlation with treatment response, Lipiodol deposition, and overall survival (OS). EXPERIMENTAL DESIGN: In this prospective single-center study, 46 patients with unresectable HCC underwent either cTACE followed by interstitial brachytherapy (iBT) after 24h (n = 23) or iBT alone (n = 23). Peripheral blood samples were obtained before treatment in both groups and 24h post-cTACE in the cTACE/iBT group. Additionally, tumor interstitial fluid (TIF) was isolated from tumor biopsies that were collected prior to iBT from untreated tumors (iBT group) or 24h post-cTACE (cTACE/iBT group). Serum and TIF cytokines were quantified using multiplex assays and correlated with radiologic response at 8-week MRI, Lipiodol patterns on CT 24h post-cTACE, and OS. RESULTS: Post-cTACE, serum IFN-γ, MCP-1, TNF-α, MIP-1α, IL-17, IL-8, IL-4, and IL-5 significantly decreased, while IL-6 increased (p < 0.005). TIF analysis showed higher IL-17 in untreated tumors compared to post-cTACE (p = 0.038), but differences were modest. In the iBT group, responders had elevated TIF IL-8 (p = 0.0103) and VEGF-A (p = 0.0185) prior to treatment, whereas in the cTACE/iBT group, responders exhibited lower TIF bFGF post-cTACE than non-responders (p = 0.0449). Elevated baseline serum IL-6 (p = 0.052), IL-8 (p = 0.036), and IFN-γ (p = 0.0508) were associated with shorter OS, while higher TIF IFN-γ (p = 0.051) correlated with improved OS. Baseline serum IL-1β (p = 0.0266) and post-cTACE serum level of VEGF-A (p = 0.0318) were higher in patients with homogeneous Lipiodol deposition in tumors, which correlated with longer OS. CONCLUSIONS: cTACE induces distinct systemic and local immune alterations that influence patient outcomes. Specifically, elevated serum IL-6 predicted poor survival, while homogeneous Lipiodol deposition marks favorable immune modulation and outcomes. Combining cytokine profiling with imaging biomarkers may enable improved, personalized treatment strategies in HCC.