A classification based on tumor budding and immune score for patients with hepatocellular carcinoma - PubMed (original) (raw)

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

Li Wei et al. Oncoimmunology. 2019.

Abstract

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: ISA-TBhigh (type I), ISB-TBhigh (type II), ISA-TBlow (type III) and ISB-TBlow (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 (ISATBhigh) patients, while IS-TB type IV (ISBTBlow) 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.

Keywords: Hepatocellular carcinoma; immune score; prognosis; tumor budding; whole exome sequencing.

© 2019 The Author(s). Published with license by Taylor & Francis Group, LLC.

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Figures

Figure 1.

Figure 1.

Flowchart of the study design. Tumor budding was graded into grade 1 (0–4), grade 2 (5–9) and grade 3 (≥10). In addition, cases with ≥10 buds were classified as high-grade tumor budding, those with 0 to 9 buds were classified as low-grade tumor budding. HCC-specific pathological patterns were also confirmed in Hematoxylin-eosin-stained slides. Eleven immune biomarkers were stained by immunohistochemistry. Moreover, α-SMA and EMT markers including E-cadherin and vimentin were stained. Whole exome sequencing was performed in one hundred pairs of tumoral and non-tumoral samples.

Figure 2.

Figure 2.

Representative images of grade 1–3 tumor budding and the prognostic role of tumor budding in training and validation cohorts. (a–c), Representative images of grade 1–3 tumor budding. (d), Survival analysis comparing overall survival (OS) between tumor budding (TB)-grade-high and TB-grade-low groups in the training cohort. (e), Disease-free survival (DFS) analyses in the training cohort. (f), the forest map showed that TB was an adverse prognostic factor for both OS and DFS in the training cohort after adjusting confounding factors. (g–h), Survival analysis comparing OS (G) and DFS (H) between tumor TB-grade-high and TB-grade-low groups in the validation cohort. (i), the forest map showed that TB was an adverse prognostic factor for both OS and DFS in the validation cohort. AFP, alpha fetoprotein; HBV, hepatitis-B virus; ALBI, albumin-bilirubin; BCLC, Barcelona Clinic Liver Cancer staging system; MVI, microvascular invasion.

Figure 3.

Figure 3.

Associations of tumor budding with pathological and immune features. (a) representative images of E-cadherin, vimentin, α-SMA and stromal maturity. (b) Associations of tumor budding with E-cadherin and vimentin expressions (E-cadherin and vimentin were divided into high and low groups by the median values of expression levels). (c) Associations of tumor budding with stromal features including α-SMA expression and tumor maturity. (d) Associations of tumor budding with HCC pathological patterns including pseudoglandular, trabecular, steatotic, cirrhotic-HCC and tumor differentiation. (e) the heat map shows the main immune cell infiltrations linked to tumor budding grade. PDL1-I, PDL1-immune cells.

Figure 4.

Figure 4.

Associations of tumor budding with immune cell infiltrations. (a–f) representative images of CD3, CD8, CD20, CD45RO, CD45RA, and CD57. (g) Associations of tumor budding grade with expressions of CD3, CD8, CD20, CD45RO, CD45RA and CD57 in the tumor samples. (h–l), representative images of FOXP3, PD-L1, PD1, CD68 and mast cells. (m) Associations of tumor budding grade with expressions of FOXP3, PD-L1, PD1, CD68 and mast cells.

Figure 5.

Figure 5.

Survival analyses comparing the overall and disease-free survival among four HCC subgroups classified by IS-TB type. (a) overall survival in the training cohort. (b) disease-free survival in the training cohort. (c) overall survival in the validation cohort. (d) disease-free survival in the validation cohort.

Figure 6.

Figure 6.

Summary of the molecular, immune and pathological characteristics in the 100 patients receiving whole-exome sequencing. Patients were clustered based on IS-TB types.

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