Complex interaction networks of cytokines after transarterial chemotherapy in patients with hepatocellular carcinoma

Treating hepatocellular carcinoma with transarterial chemoembolization (TACE) induces both local inflammation in the tumor microenvironment as well as systemic inflammation. We analyzed serum cytokine response to TACE to evaluate this. Serum samples obtained from 203 HCC patients treated with TACE were analyzed for inflammatory cytokines including interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12, IL-13, IL-17, IL-22, TNF-α, IFN-γ, and C-reactive protein (CRP) levels. Cytokine concentrations were measured at day 0 (D0, baseline, n = 203), day3 (D3, n = 156), day7 (D7, n = 147), and day 60 (D60, n = 115) after TACE. Network analysis of the cytokines was performed to understand their interactive relationship. After TACE, IL-1β, -6,-9, -12, and -22 increased by D60. IL-2, -5, -10, -17A and INF-γ decreased by D60, and IL-4, -13 and TNF-α revealed stable concentration. D0 network revealed that IL-2, -4, -5, and -10 formed a module. D3 network had the highest clustering coefficient and average degree that revealed similar pattern as CRP. D7 network revealed that IL-6, -9 and CRP were isolated from the network. D60 network had the lower network heterogeneity and lower clustering coefficient, network diameter, shortest path and characteristic path length. Degree correlation revealed that assortative network turned to disassortative network by D60 indicating that the network gained scale free feature. D60 cytokine network retained inflammatory function and these parameters indicated that the systemic inflammation induced by TACE appeared to be attenuated by D60. IL-9 at D3 and D7 seemed to be related to anti-tumor effect and IL-6 at D7 and D60, and IL-22 at D60 was related to regenerative but not pro- or anti- inflammatory function. Median survival month of patient group with high and low values of cytokine with P-values were as follows: D0 CRP, 9.5 and 54.2 months (P<0.0001); D0 IL-2, 39.9 and 56.1 months (P = 0.0084); D3 CRP, 31.3 and 55.1 months (P = 0.0056); D7 CRP, 28.7 and 50.7 months (P = 0.0065), respectively. TACE is associated with systemic inflammation which appears to peak at Day 3 and resolve by D60. Among the tested cytokines, IL-6 and IL-22 appear to play a regenerative role.