Herpesvirus entry mediator as a potential biomarker in breast cancer compared with conventional cytotoxic T‑lymphocyte‑associated antigen 4

Abstract

Breast cancer (BC) is the most common cancer in women worldwide, with 2.3 million cases recorded in 2020. Despite improvements in cancer treatment, patients with BC still succumb to the disease, due to regional and distant metastases when diagnosed at later stages. Several immune checkpoint inhibitors have been approved for BC treatment, based on their expression and role in maintaining immunosurveillance against tumors. The present study aimed to evaluate the expression of 12 immune checkpoints in patients with BC, and assess their role as diagnostic and therapeutic markers. Expression levels were measured using reverse transcription-quantitative polymerase chain reaction. Among the 12 immune markers, herpesvirus entry mediator (HVEM) was found to be significantly upregulated in patients with malignant BC compared to non-malignant controls, with a relative fold change (FC) of 1.46 and P=0.012. A similar finding was observed for cytotoxic T-lymphocyte-associated antigen 4 (CTLA4; FC=1.47 and P=0.035). In addition, receiver operating characteristic curve analysis revealed that HVEM expression allowed significant differentiation between groups, with an area under the curve of 0.74 (P=0.013). Upregulation in both HVEM and CTLA4 was revealed to be significantly associated with the human epidermal growth factor receptor-2 (HER2)-enriched phenotype (FC=3.53, P=0.009 and FC=5.98, P=0.002, respectively), while only HVEM was significantly associated with the triple-negative phenotype (FC=2.07, P=0.016). Furthermore, HVEM was significantly higher in patients with grade III tumors (FC=1.88, P=0.025) and negative vascular invasion (FC=1.67, P=0.046) compared with non-malignant controls. Serum protein levels were assessed by multiplex immunoassay, and a significant increase in HVEM was detected in patients with malignant BC compared with that in non-malignant controls (P=0.035). These data indicated that HVEM may serve as a potential biomarker and target for immunotherapy, especially for certain types of BC.

Herpesvirus Entry Mediator as an Immune Checkpoint Target and a Potential Prognostic Biomarker in Myeloid and Lymphoid Leukemia

“…Moreover, various programs were employed to analyze data, such as FlowJo for flow cytometric data and GraphPad Prism for statistical analysis [30,35]. The results included in this study indicate whether the differences between groups are significant based on p-values [12]. The consistency, stability, and repeatability of the experiment's results confirm the reliability of our study.…”

“…In addition, newly diagnosed ALL patients have upregulated HVEM expression. Moreover, we have previously shown a positive correlation between HVEM gene expression and HVEM serum levels in breast cancer with a higher tumor grade and a worse cancer prognosis [12,28]. The serum levels of HVEM are elevated compared with serum CTLA-4 in breast cancer PBMCs.…”

“…All participants or legal guardians were informed of the objective of the study and were required to sign a consent form before participating in the study. An amount of 3-5 mL of peripheral blood samples was collected into EDTA tubes using PAXgene™ blood RNA tubes (BRT; Qiagen, Inc.) according to the manufacturer's instructions [12]. The collected blood samples were stored at −80 • C and used for RNA extraction.…”

“…It has a broader expression than the well-known PD-1, which is approved for cancer immunotherapy targets [11]. Further, peripheral blood mononuclear cells (PBMCs) of breast cancer patients express the HVEM gene in similar levels to the approved target immunotherapy CTLA-4 [12].…”