Expression And Clinical Value Of PD-1, CTLA-4 In Patients With Hepatocellular Carcinoma

[Objective]To analyze the clinical data and survival information of patients with hepatocellular carcinoma radical excision, to detect the expression of PD-1 and CTLA-4 proteins, to explore the relationship of the two kinds of protein expression and chinicopathological features above, and to analyze their influences on patients’ prognosis, with the aim to find novel biomarkers to predict recurrence and metastasis risk and death risk of patients’which can provide new theoretical foundation.[Method]Cases with post operation of hepatocellular carcinoma radical excision and with complete clinical data and follow-up information ranging time from Jan 2004 to Dec 2010 were collected, the surgical pathological specimens were made into tissue microarray. Expression of PD-1 and CTLA-4 were detected by tissue microarray and immunohistochemistry. The relationship among these clinicopathological features, proteins expression and prognosis were analyzes by SPSS21.0 software package.[Result]1. Two hundreds and forty cases after hepatocellular carcinoma radical excision were enrolled.179 patients (74.6%) had experienced tumor recurrence or metastasis, while 173 patients (72.1%) had died. The median DFS was 10.9 months, and the median OS was 29.3 months.2. PD-1 and CTLA-4 were mainly expressed in tumor cells within cancer tissues, and in hepatocytes within adjacent tissues. Little PD-1 and no CTLA-4 expression were observed in tumor-infiltrating lymphocytes.3. PD-1 and CTLA-4 were expressed much higher in adjacent tissues than in tumor tissues, significantly (P=0.000, P=0,000).4. PD-1 expressed in tumor tissue was significantly different among albumin levels (P=0.022), while PD-1 in adjacent tissues was different among hepatic virus and TNM stages (P=0.028, P=0.038). CTLA-4 in tumor tissues was different among symptoms, AFP levels, histologic differentiation, maximal tumor diameter and partial necrosis (P=0.031, P=0.000, P=0.000, P=0.001, P=0.006), while CTLA-4 in adjacent tissues was different among tumor numbers (P=0.031).5. Expression of PD-1 in tumor tissues was associated with that in adjacent tissues (P=0.000). In tumor tissues, PD-1 expression was associated CTLA-4 (P=0.000), so did in adjacent tissues (P=0.000).6. Patients with higher expression of PD-1 in tumor tissues had longer OS than those with lower PD-1 expression (P=0.034), and their DFS had no differences. Patients with higher CTLA-4 expression in tumor tissues had longer DFS and OS than those with lower expression (DFS:P=0.002, OS:P=0.002). Patients with higher co-expression of PD-1 and CTLA-4 in tumor tissues had longer DFS and OS than those only with higher PD-1 or higher CTLA-4, while those only with higher PD-1 or higher CTLA-4 had longer DFS and OS than those with both lower expression (DFS: P=0.002, OS:P=0.000).The co-expression of PD-1 and CTLA-4 had no influence on DFS or OS.7. Lower co-expression of PD-1 and CTLA-4 was an independent risk factor of recurrence or metastasis and of death. Aside from that, risk factors of OS also included lower histologic differentiation, over 3 tumors, larger tumor diameter, portal vein thrombosis and partial necrosis.[Conclusion]1. PD-1 and CTLA-4 are mainly expressed in tumor cells within tumor area, and in hepatocytes within adjacent tissues. PD-1 and CTLA-4 are expressed much higher in adjacent tissues than in tumor tissues.2. Lower co-expression of PD-1 and CTLA-4 are an independent risk factor of recurrence or metastasis and of death, which suggests immune checkpoint being a more complicated role in hepatocellular carcinoma, and calls for more evidences.3. Risk factors of OS also include lower histologic differentiation, over 3 tumors, larger tumor diameter, portal vein thrombosis and partial necrosis.