Association of Increased Programmed Death Ligand 1 Expression and Regulatory T Cells Infiltration with Higher Hepatocellular Carcinoma Recurrence in Patients with Hepatitis B Virus Pre-S2 Mutant after Curative Surgical Resection

Abstract

Although surgical resection is available as a potentially curative therapy for hepatocellular carcinoma (HCC), high recurrence of HCC after surgery remains a serious obstacle for long-term patient survival. Therefore, the discovery of valuable prognostic biomarkers for HCC recurrence is urgently needed. Pre-S2 mutant is a mutant form of hepatitis B virus (HBV) large surface protein which is expressed from the HBV surface gene harboring deletion mutations spanning the pre-S2 gene segment. Pre-S2 mutant-positive HCC patients have been regarded as a high-risk population of HCC recurrence after resection surgery and display increased immune checkpoint programmed death ligand 1 (PD-L1) expression and pro-tumor regulatory T cells (Tregs) infiltration in tumor tissues. In this study, the association of higher levels of PD-L1 expression and Tregs infiltration in tumor tissues with post-operative HCC recurrence in pre-S2 mutant-positive HCC patients was evaluated. We found that patients with pre-S2 mutant in combination with higher levels of PD-L1 expression and Tregs infiltration in tumor tissues were independently associated with a higher risk of HCC recurrence (hazard ratio, 4.109; p value = 0.0011) and poorer recurrence-free survival (median, 8.2 versus 18.0 months; p value = 0.0004) than those of patients with either one or two of these three biomarkers. Furthermore, a combination of pre-S2 mutant, intra-tumoral PD-L1 expression, and tumor-infiltrating Tregs exhibited superior performance in identifying patients at a higher risk of HCC recurrence (area under the receiver operating characteristic curve, 0.8400). Collectively, this study suggests that higher levels of PD-L1 expression and Tregs infiltration in tumor tissues predicted a higher risk of HCC recurrence in pre-S2 mutant-positive HCC patients after curative surgical resection.

Increased plasma levels of monocyte chemoattractant protein‐1 in patients with hepatitis B virus pre‐S2 gene deletion mutation predict a higher risk of hepatocellular carcinoma recurrence after curative surgical resection

“…25,26 Moreover, the presence of pre-S2 gene deletion mutation in combination with high levels of PD-L1 expression and Treg infiltration have been correlated with a higher risk of HCC recurrence after curative surgical resection than either one or two of these three biomarkers. 27 However, to date, the relationship between pre-S2 gene deletion mutation and cytokine expression levels in HBV-related HCC patients remains largely unknown. Therefore, to identify the cytokines with altered expression levels in HBV-related HCC patients with pre-S2 gene deletion mutation would be promising for not only providing new insights into pre-S2 mutant regulation of tumor immune microenvironment (mediation through upregulation of cancer-promoting cytokines or downregulation of cancer-inhibiting cytokines) but also discovering potential biomarkers to be combined with pre-S2 gene deletion mutation for better prediction of poor patient prognosis.…”

“…Recently, it has been shown that HCC patients with pre‐S2 gene deletion mutation have significantly higher expression of the immune checkpoint molecule programmed death ligand 1 (PD‐L1) and higher infiltration of the anti‐inflammatory lymphocyte regulatory T cells (Tregs) in tumor tissues than patients without pre‐S2 gene deletion mutation, suggesting the association of pre‐S2 gene deletion mutation with dysregulated tumor immune microenvironment in HBV‐related HCC 25,26 . Moreover, the presence of pre‐S2 gene deletion mutation in combination with high levels of PD‐L1 expression and Treg infiltration have been correlated with a higher risk of HCC recurrence after curative surgical resection than either one or two of these three biomarkers 27 . However, to date, the relationship between pre‐S2 gene deletion mutation and cytokine expression levels in HBV‐related HCC patients remains largely unknown.…”

Special Issue “New Frontiers in Small DNA Virus Research”

“…As the cervical microbiota are important factors for disease progression, this study suggests further studies to ascertain the role of other viruses as cofactors in carcinogenesis and/or markers of disease progression. Jeng et al report that deletion mutations in the HBV surface protein pre-S2, increased levels of PD-L1 expression, and regulatory T (Treg) cell infiltration into the tumor tissues may help to predict a high risk for recurrence of hepatocellular carcinoma (HCC) [ 2 ]. Next, Koubek et al provide promising results showing that natural compounds in the schweinfurthin family can be used as chemotherapeutic agents to treat Merkel cell carcinoma (MCC) [ 3 ].…”