Expression and significance of programmed death-1 and T-cell immunoglobulin-and mucin domain-3-containing molecule 3 in hepatocellular carcinoma

Objective To investigate the expression and clinical significance of programmed death-1(PD-1) and T-cell immunoglobulin-and mucin domain-3-containing molecule 3(TIM-3) in hepatocellular carcinoma(HCC).Methods The paraffin blocks of HCC tissue and adjacent tissue(> 1 cm from the tumor margin) were collected from 46 patients with HCC who underwent surgical treatment in No.900 Hospital of The Joint Service and Security Force of The Chinese People's Liberation Army from January 2013 to December 2015.Immunohistochemistry was used to measure the expression of PD-1 and TIM-3,and their association with clinicopathological features and prognosis was analyzed.The Wilcoxon test was used for comparison of paired ranked data,and a Spearman correlation analysis was used to investigate the correlation between ranked data; the Kaplan-Meier method was used for survival analysis,and the log-rank test was used for comparison of survival rates between groups; the Cox regression model was used to perform a multivariate analysis.Results The expression levels of PD-1 and TIM-3 in HCC tissue were higher than those in adjacent tissue(both P<0.05).PD-1 was mainly localized in lymphocytes and TIM-3 was mainly localized in tumor-associated macrophages.The expression of PD-1 was positively correlated with that of TIM-3 in HCC tissue(rs=0.397,P=0.006).The expression level of PD-1 in HCC tissue was associated with tumor size(rs=0.480,P=0.001),portal vein tumor thrombus(rs=0.307,P=0.038),and TNM stage(rs=0.534,P <0.001),and the expression level of TIM-3 was associated with portal vein tumor thrombus(rs=0.301,P=0.042),degree of pathological differentiation(rs=0.356,P=0.015),and TNM stage(rs=0.416,P=0.004).For the patients with HCC,the 1-,3-,and 5-year overall survival rates were89.1%,56.5%,and 34.4%,respectively,and the 1-,3-,and 5-year disease-free survival rates were 52.2%,21.7%,and 10.9%,respectively.The multivariate analysis showed that degree of pathological differentiation(hazard ratio [HR]=4.723,95% confidence interval [CI]:1.618-7.684,P=0.001),tumor size(HR=3.234,95% CI:1.327-7.883,P=0.010),TNM stage(HR=3.254,95% CI:1.076-9.835,P=0.037),and expression level of TIM-3(HR=0.572,95% CI:0.329-0.995,P=0.048) were independent prognostic factors for the overall survival of HCC patients,and degree of pathological differentiation(HR=2.945,95% CI:1.527-5.682,P=0.001) and TNM stage(HR=2.074,95% CI:1.259-9.793,P=0.016) were independent prognostic factors for the disease-free survival of HCC patients.Conclusion High expression levels of both PD-1 and TIM-3 are observed in HCC tissue,and PD-1 and TIM-3 may be involved in the progression and poor prognosis of HCC patients.