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

Abstract

<b><i>Introduction:</i></b> 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. <b><i>Methods:</i></b> 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 β-catenin and those without the mutations using transcriptome-based immunogram. <b><i>Results:</i></b> Univariate analysis showed that the disease control rate was significantly better in patients with α-fetoprotein < 400 ng/mL, negative for β-catenin/glutamate synthetase (GS) staining, high combined positive score (CPS) of programmed death-ligand 1 (PD-L1), and increased infiltration of CD8<sup>+</sup> cells in tumor tissues. Among them, negative staining of β-catenin/GS, CPS of PD-L1 ≥ 1, and high degree of CD8<sup>+</sup> 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 (<i>p</i> < 0.0001 and <i>p</i> = 0.0048 for PFS and OS, respectively). In addition, the immunogram revealed that tumor-carrying mutations in β-catenin showed downregulation of immune-related genes, especially in those related to priming and activation by dendritic cells, interferon-γ response, inhibitory molecules, and regulatory T cells. <b><i>Discussion/Conclusion:</i></b> The combined score including Wnt/β-catenin activation, CPS of PD-L1, and degree of CD8<sup>+</sup> TILs in HCC is informative for predicting the response to ICI in HCC cases. Constitutive activation of β-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.

Interleukin-6 Is a Circulating Prognostic Biomarker for Hepatocellular Carcinoma Patients Treated with Combined Immunotherapy

“…Regarding other liquid biopsy biomarkers for the efficacy of immunotherapy, genetic alterations affect the immune cell infiltration pattern and thus might affect the efficacy of immunotherapy [ 27 ]. The WNT/CTNNB1 signaling pathway was recently reported to suppress immune cell infiltration [ 28 , 29 ], and this signaling activation in the tumor site was negatively associated with ICI treatment in HCC [ 30 ]. In the present study, we analyzed the plasma levels of DKK1, which is an antagonist of WNT signaling, as a potential surrogate marker of WNT/CTNNB1 signaling activity, but they were not associated with the response to Atezo/Bev therapy.…”

A FAK Inhibitor Boosts Anti-PD1 Immunotherapy in a Hepatocellular Carcinoma Mouse Model

“…High expression of PD-L1 may lead to the suppression of immune function ( Topalian et al, 2016 ; Li et al, 2019 ). However, clinical studies have shown that patients with increased CD8 + T cell infiltration and high PD-L1 positivity in HCC are more sensitive to anti-PD1 therapy and have a significantly improved disease control rate, which is significantly associated with prolonged PFS and OS ( Aguiar et al, 2018 ; Han et al, 2019 ; Morita et al, 2021 ). The combination of VS4718 and an anti-PD1 antibody can not only increase the infiltration of CD8 + T cells and reduce the infiltration of immunosuppressive Tregs and macrophages but also block the binding of PD1 on the surface of T cells to PD-L1 on the surface of tumor cells.…”

Combination Immunotherapy with Anti-PD-1/PD-L1 Antibody plus Anti-VEGF Antibody May Promote Cytotoxic T Lymphocyte Infiltration in Hepatocellular Carcinoma, Including in the Noninflamed Subclass

“…Immunotherapy may have completely opposite effects in these two distinct subclasses with CTNNB1 mutations. In other words, the immune-like subclass with the phenotype characterized by prominent infiltration of immune cells (e.g., infiltrations of CD8+ T cells, increases in M1 macrophages, and IFN-γ signature), and the immune-excluded subclass with the completely opposite phenotype will respond to immunotherapy very differently [16].…”