Prognostic value of tumor-infiltrating lymphocytes in hepatocellular carcinoma

BACKGROUND: In patients with hepatocellular carcinoma (HCC), the prognostic role of tumor-infiltrating lymphocytes (TILs) for survival is still controversial. A meta-analysis was performed to investigate the prognostic effect of TILs in HCC. METHODS: We identify studies from PubMed, Embase, and the Cochrane Library to evaluate the prognostic value of TILs in patients with HCC. A meta-analysis was conducted to estimate overall survival and disease-free survival. The hazard ratio (HR) and 95% confidence interval (CI) were calculated employing fixed-effect or random-effect models depending on the heterogeneity of the included trials. RESULTS: A total of 7905 patients from 46 observational studies were enrolled. For TILs subsets, the density of CD8+, FOXP3+, CD3+, and Granzyme B+ lymphocytes was significantly associated with improved survival (P < .05). The density of FOXP3+ TILs in intratumor (IT) was the most significant prognostic marker (pooled HR = 1.894; 95% CI = 1.659-2.164; P < .001). Patients with high infiltration of CD8+ TILs in IT (pooled HR = 0.676; 95% CI = 0.540-0.845; P = .001) or in margin of tumor (MT) (pooled HR = 0.577; 95% CI = 0.437-0.760; P < .001) had better OS. The pooled analysis revealed that high density of Granzyme B+ T-lymphocytes in IT was statistically significant associated with better OS (pooled HR = 0.621; 95% CI = 0.516-0.748; P < .001) and DFS (pooled HR = 0.678; 95% CI = 0.563-0.815; P < .001). It was interesting that high density of CD3+ in IT foreboded worse OS (pooled HR = 1.008; 95% CI = 1.000-1.015; P = .037), but better DFS (pooled HR = 0.596; 95% CI = 0.374-0.948; P = .029). CONCLUSION: Our findings suggested that some TIL subsets could serve as prognostic biomarkers in HCC. High-quality randomized controlled trials are needed to determine if these TILs could serve as targets for immunotherapy in HCC.