A classification based on tumor budding and immune score for patients with hepatocellular carcinoma

Background: The role of immune profiling and tumor budding in hepatocellular carcinoma (HCC) remains largely unknown. This study evaluated the association between tumor budding and lymphocytic infiltration in HCC. Meanwhile, HCC patients were stratified based on tumor budding grade and immune score. Patients and methods: A total of 423 HCC patients were divided into training (n = 212) and validation (n = 211) cohort. Tumor slides from resected HCC samples were used for tumor budding assessment. A prognosis-relevant immune score was developed based on five types of immune cells out of eleven immune markers. A classification based on tumor budding grade and immune type was established (IS-TB type). To explore the association of IS-TB type and molecular alterations of HCC, 100 HCC samples and adjacent non-tumor tissues from 100 patients were investigated by whole-exome sequencing. Results: Tumor budding was an independent adverse prognostic factor for OS and DFS in both of the training and validation cohorts (all P values <.05). The rate of high-grade tumor budding was significantly higher in HCC with immature stroma (P < .001), strong α-SMA expression (P = .005), non-steatotic tumors and non-fibrolamellar-HCC (P < .001). Additionally, tumor budding was related to both anti- and pro-tumor immune responses. Patients were classified into immune type A and immune type B according to the immune score. Based on tumor budding grade and immunotype, patients were classified into four subgroups: IS(A)-TB(high) (type I), IS(B)-TB(high) (type II), IS(A)-TB(low) (type III) and IS(B)-TB(low) (type IV). Patients with type III tumor had the best OS and DFS, whereas OS and DFS were the worst for cases with type II tumor. TP53 mutation was more frequent in IS-TB type I (IS(A)TB(high)) patients, while IS-TB type IV (IS(B)TB(low)) harbored high number of CTNNB1 mutation. Conclusion: Tumor-immune cell interactions in HCC is heterogeneous. HCC classification based on tumor budding and immune score correlates with patient survival and molecular alterations. The defined subtypes may have significance for utilizing individualized treatment in patients with HCC.