Hepatitis B virus-triggered PTEN/β-catenin/c-Myc signaling enhances PD-L1 expression to promote immune evasion

Abstract

Hepatitis B virus (HBV) exploits multiple strategies to evade host immune surveillance. Programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) signaling plays a critical role in regulating T cell homeostasis. However, it remains largely unknown as to how HBV infection elevates PD-L1 expression in hepatocytes. A mouse model of HBV infection was established by hydrodynamic injection with a vector containing 1.3-fold overlength HBV genome (pHBV1.3) via the tail vein. Coculture experiments with HBV-expressing hepatoma cells and Jurkat T cells were established in vitro. We observed significant decrease in the expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and increase in β-catenin/PD-L1 expression in liver tissues from patients with chronic hepatitis B and mice subjected to pHBV1.3 hydrodynamic injection. Mechanistically, decrease in PTEN enhanced β-catenin/c-Myc signaling and PD-L1 expression in HBV-expressing hepatoma cells, which in turn augmented PD-1 expression, lowered IL-2 secretion, and induced T cell apoptosis. However, β-catenin disruption inhibited PTEN-mediated PD-L1 expression, which was accompanied by decreased PD-1 expression, and increased IL-2 production in T cells. Luciferase reporter assays revealed that c-Myc stimulated transcriptional activity of PD-L1. In addition, HBV X protein (HBx) and HBV polymerase (HBp) contributed to PTEN downregulation and β-catenin/PD-L1 upregulation. Strikingly, PTEN overexpression in hepatocytes inhibited β-catenin/PD-L1 signaling and promoted HBV clearance in vivo. Our findings suggest that HBV-triggered PTEN/β-catenin/c-Myc signaling via HBx and HBp enhances PD-L1 expression, leading to inhibition of T cell response, and promotes HBV immune evasion. NEW & NOTEWORTHY This study demonstrates that during HBV infection, HBV can increase PD-L1 expression via PTEN/β-catenin/c-Myc signaling pathway, which in turn inhibits T cell response and ultimately promotes HBV immune evasion. Targeting this signaling pathway is a potential strategy for immunotherapy of chronic hepatitis B.

2,5-dimethylcelecoxib improves immune microenvironment of hepatocellular carcinoma by promoting ubiquitination of HBx-induced PD-L1

“…With regard to the relationship among HBx, PD-L1 and CD8 + T cells, some scholars believed that HBx upregulates the transcription level of B7-H1 gene through transcription factor NF-κB, which leads to the increase of PD-L1 protein expression and promotes T cells apoptosis. 22 Sun et al 23 proved that HBx can activate the transcriptional activity of B7-H1 through PTEN/β-catenin/c-Myc signal pathway and increase the expression of PD-L1, which can inhibit T cells response and promote HBV immune escape. These studies analyzed the mechanism of HBV factor affecting T cells function through PD-L1 from different signal pathways.…”

Phosphatase and Tensin Homolog in Non-neoplastic Digestive Disease: More Than Just Tumor Suppressor

“…In addition, the interactions between PTEN polymorphisms and HBV mutations may help identify individuals who are susceptible to HCC (Du et al, 2015). HBx and HBV polymerase (HBp) were shown to enhance PD-L1 expression through PTEN-dependent pathway, which induces inhibition of T cell response and promotes virus immune evasion in mice (Sun et al, 2020).…”

Depleting Tumor Cells Expressing Immune Checkpoint Ligands—A New Approach to Combat Cancer

“…Copy number alterations in chromosomal region 9p24.1 that encompasses the loci for PD-L1 and PD-L2, inversions, deletions, translocations, generation of chimeric fusion transcripts, and disruption or mutation of the 3 -untranslated region of the PD-L1 gene are intrachromosomal events that can lead to PD-L1 overexpression [10][11][12]. Tumor cell-autonomous, extrachromosomal events are receptor-activating mutations or receptor overexpression [13], gain-of-function or loss-of-function mutations affecting intracellular signaling molecules [14,15], activation or overexpression of transcription factors (e.g., hypoxia-inducible factor-α, signal transducer and activator of transcription (STAT) 3, MYC) [16][17][18]. More recently, also epigenetic mechanisms have been reported to induce or contribute to the overexpression of tumor cell-associated PD-L1 [19,20].…”