Highly elevated soluble Tim-3 levels correlate with increased hepatocellular carcinoma risk and poor survival of hepatocellular carcinoma patients in chronic hepatitis B virus infection

Background and objective: Upregulated T-cell immunoglobulin and mucin domain containing molecule-3 (Tim-3) in hepatitis B virus (HBV)-specific CD8(+) T-cells contributes to CD8(+) T-cell exhaustion during chronic HBV infection. The membrane-bound Tim-3 can be cleaved from the cell surface by sheddase, yielding soluble Tim-3 (sTim-3). This study investigated serum sTim-3 levels in patients with chronic HBV infection of various liver diseases. Methods: Serum sTim-3 levels were quantitatively determined in 288 patients with chronic HBV infection of various liver diseases. The sTim-3 levels were analyzed in relation to liver diseases including HBV-related hepatocellular carcinoma (HCC) and overall survival of HCC patients. Results: Serum sTim-3 levels in the patients with chronic HBV infection were significantly elevated compared with healthy controls (P< 0.001) and the levels from asymptomatic HBV carrier status, chronic hepatitis, liver cirrhosis to HCC were progressively increased. Serum sTim-3 levels were closely associated with the severity of liver function abnormalities. Importantly, serum sTim-3 levels were independently associated with HCC risk (OR, 4.310; 95% CI, 2.141-8.676, P< 0.001) in comparison to non-HCC diseases in chronic HBV infection and significantly associated with the overall survival of HCC patients, with a level > 3000 pg/mL being related to shorter overall survival than a level <= 3000 pg/mL (P=0.019). Conclusion: Serum sTim-3 is involved in disease progression and HCC development in chronic HBV infection and its quantitative determination may be potentially used as a marker for monitoring the disease progression and predicting the HCC prognosis in chronic HBV infection.