Elevated Pretherapy Serum IL17 in Primary Hepatocellular Carcinoma Patients Correlate to Increased Risk of Early Recurrence after Curative Hepatectomy

Abstract

Background and AimsPrimary hepatocellular carcinoma (HCC) is usually presented in inflamed fibrotic/cirrhotic liver with extensive lymphocyte infiltration. We examined the associations between the HCC early recurrence and alterations in serum levels of inflammatory cytokines.MethodsA cohort of 105 HCC patients with chronic hepatitis B virus infection were included. Pre-therapy, we quantified their serum concentrations of Th1-, Th2-, Th17-, Treg-related, and other cytokines that have been reported to be associated with poor prognosis in human cancers. IL17-producing T-cells were generated in vitro from HCC patients and co-cultured with HCC cell lines separated by a 0.4 µM transwell.ResultsAll the 105 cases of HCC patients had liver cirrhosis. The patients who suffered from HCC early recurrence had higher pre-therapy serum levels of IL17 and lower levels of IL10 than those who did not suffer from recurrence after curative hepatectomy. After adjustment for general tumor clinicopathological factors, elevated serum levels of IL17 (≥0.9 pg/ml) was found to be an independent risk factor for HCC early recurrence with a hazard ratio of 2.46 (95%CI 1.34–4.51). Patients with bigger tumors (>5 cm in diameter) and elevated serum levels of IL17 had the highest risk of early recurrence as compared to those with only one of these factors (P = 0.009) or without any (P<0.001). These factors showed similar effects on the HCC patient overall survival. Intrahepatic infiltrated T-cells in HCC patients were identified as the major IL17-producing cells. Proliferation of HCC cells, QGY-7703, was augmented QGY-7703, was augmented in the presence of IL17-producing T-cells. This effect diminished after neutralizing antibody against human IL17A or TNFα was included.ConclusionBoth tumors and IL17 from liver infiltrated T-cells contributed to HCC early recurrence and progression after curative resection. Pre-therapy serum IL17 levels may serve as an additional indicator for predicting high-risk patients.

The correlations between IL-17 vs. Th17 cells and cancer patient survival: a systematic review

“…Potential risks of bias identified in categorizing IL-17 or Th17 expression were optimal cut-off values chosen arbitrarily 15,16 or using a minimum p value, 17-23 receiver operating characteristic (ROC) curve [24][25][26][27] or regression tree analysis. 28 Furthermore, one study compared the six long (>3 y) vs. short (<1.5 y) surviving patients.…”

“…Five studies out of ten reported that a high amount of serum IL-17 protein was correlated with poor survival. 17,[24][25][26]31 One study showed a correlation between high IL-17 and improved survival in leukemia. 32 Four studies did not observe a significant correlation between high serum IL-17 levels and survival, [33][34][35][36] although one group did find a trend toward poor prognosis (p D 0.05).…”

Safety Profile of Secukinumab in Treatment of Patients with Psoriasis and Concurrent Hepatitis B or C: A Multicentric Prospective Cohort Study

“…Previous studies have suggested that IL-17 is associated with increased risk of tumorigenesis, invasiveness and metastasis (38)(39)(40). Increased pretreatment levels of IL-17 were also associated with poor prognosis and early recurrence of HCC (38).…”

“…Increased pretreatment levels of IL-17 were also associated with poor prognosis and early recurrence of HCC (38). Nevertheless, some researchers suggested that L-17A play a role of enhancing the immune system against tumorigenesis (41,42).…”

Control of oxidative stress in hepatocellular carcinoma: Helpful or harmful?

“…Elevated pre-therapy serum IL-17 levels in patients with HCC correlate with risk of early recurrence after curative hepatectomy [84] . Cocultured HCC cell lines and T cells producing IL17 in vitro augment the proliferation of HCC cells, suggesting the importance of IL17 for HCC pathogenesis.…”