Author：Haibei Xin, Huan Chen, Lihong Wu, Yanhui Chen, Hongli Luo, Henghui Zhang, Nan Li
Background: The achievements of immune checkpoint blockade strengthen the concept that tumor outgrowth and development are comprehensively regulated by immune system. The aim of the study was to explorer whether distinct infiltrated immune cell features differentially affect clinical outcome in hepatocellular carcinoma (HCC).
Methods: We obtained respectable stage II HCC specimens, along with adjacent para-tumor tissues from 221 patients who underwent surgical resection at Eastern Hepatobiliary Surgery Hospital, (in Shanghai, China) from 2015 through April 2018. CD8+ and CD68+ tumor-infiltrating lymphocytes (TILs) in the cancer area (CA) and stroma area (SA), as well as PD-1/PD-L1 expression, were analyzed by multiple immunohistochemistry.
Results: The density of CD8+ TILs were significantly associated with gender, tumor size, and cirrhosis; while the density of CD68+ TILs were associated with copies of HBV DNA and anti-viral treatment. Multivariate Cox regression analysis revealed that high densities of CD8+ TILs and low densities of CD68+/CD8+ ratios independently predicted better outcomes. Of note, a prognostic signature combining clinic features [portal vein tumor thrombus (PVTT) and tumor size (TS)] and CD8+ TILs densities discriminated HCC patients into four subtypes with increasing risk of mortality: PVTT-negative/TS-small/CD8-high (6.8% of cases), PVTT-negative/TS-small/CD8-low (45.7%), PVTT-negative/TS-large (34.4%) and PVTT-positive (13.1%). Further association studies suggested that the four subgroups correlated with gender, tumor envelope, microvascular invasion (MVI), and SA-PD1 expression. Similarly, a prognostic signature combining PVTT, TS and CD68+/CD8+ ratios discriminated HCC patients into four subtypes with increasing risk of recurrence.
Conclusions: Combined immune features including CD8+ and CD68+ lymphocyte infiltration and clinic characteristics are useful prognostic biomarkers for HCC patients.