Immunological Microenvironment Predicts the Survival of the Patients with Hepatocellular Carcinoma Treated with Anti-PD-1 Antibody

Introduction: Although immune checkpoint inhibitors (ICIs) have been considered as promising agents for the treatment of advanced hepatocellular carcinoma (HCC), previous clinical trials revealed that the response to anti-programmed cell death protein 1 (anti-PD-1) monotherapy was as low as 20%. Identifying subgroups that respond well to ICIs is clinically important. Here, we studied the prognostic factors for anti-PD-1 antibody treatment based on the molecular and immunological features of HCC. Methods: Patients who were administered anti-PD1 antibody for advanced HCC at Kindai University Hospital were included. Clinicopathological backgrounds and antitumor responses were examined in 34 cases where tumor tissues before treatment were available. Transcriptome analysis was performed using 40 HCC samples obtained from surgical resection, and immune status was compared between 20 HCCs with activating mutations in beta-catenin and those without the mutations using transcriptome-based immunogram. Results: Univariate analysis showed that the disease control rate was significantly better in patients with alpha-fetoprotein < 400 ng/mL, negative for beta-catenin/glutamate synthetase (GS) staining, high combined positive score (CPS) of programmed death-ligand 1 (PD-L1), and increased infiltration of CD8(+) cells in tumor tissues. Among them, negative staining of beta-catenin/GS, CPS of PD-L1 >= 1, and high degree of CD8(+) tumor-infiltrating lymphocytes (TILs) were significantly associated with longer survival in both progression-free survival (PFS) and overall survival (OS). The combination of these factors well stratified the survival of the patients on anti-PD-1 antibody in both PFS and OS (p < 0.0001 and p = 0.0048 for PFS and OS, respectively). In addition, the immunogram revealed that tumor-carrying mutations in beta-catenin showed downregulation of immune-related genes, especially in those related to priming and activation by dendritic cells, interferon-gamma response, inhibitory molecules, and regulatory T cells. Discussion/Conclusion: The combined score including Wnt/beta-catenin activation, CPS of PD-L1, and degree of CD8(+) TILs in HCC is informative for predicting the response to ICI in HCC cases. Constitutive activation of beta-catenin can induce an immune cold phenotype with downregulation of immune-related genes, and immunohistochemistry-based evaluation is beneficial for identifying the subgroup that shows a good response to ICI. (C) 2021 The Author(s). Published by S. Karger AG, Basel

Automated summary

This study identified prognostic factors for anti-PD-1 antibody treatment in advanced HCC based on molecular and immunological features. Factors associated with better response included low alpha-fetoprotein levels, negative beta-catenin/GS staining, high CPS of PD-L1, and increased CD8(+) cell infiltration. Negative staining of beta-catenin/GS, CPS of PD-L1 >= 1, and high CD8(+) TILs were significantly associated with longer survival. These findings suggest that the combined score of Wnt/beta-catenin activation, CPS of PD-L1, and CD8(+) TILs can predict the response to ICI in HCC cases.