Blockade of HVEM for Prostate Cancer Immunotherapy in Humanized Mice

Abstract

The herpes virus entry mediator (HVEM) delivers a negative signal to T cells mainly through the B and T lymphocyte attenuator (BTLA) molecule. Thus, HVEM/BTLA may represent a novel immune checkpoint during an anti-tumor immune response. However, a formal demonstration that HVEM can represent a target for cancer immunotherapy is still lacking. Here, we first showed that HVEM and BTLA mRNA expression levels were associated with a worse progression-free interval in patients with prostate adenocarcinomas, indicating a detrimental role for the HVEM/BTLA immune checkpoint during prostate cancer progression. We then showed that administration of a monoclonal antibody to human HVEM resulted in a twofold reduction in the growth of a prostate cancer cell line in NOD.SCID.gc-null mice reconstituted with human T cells. Using CRISPR/Cas9, we showed that the therapeutic effect of the mAb depended on HVEM expression by the tumor, with no effect on graft vs. host disease or activation of human T cells in the spleen. In contrast, the proliferation and number of tumor-infiltrating leukocytes increased following treatment, and depletion of CD8+ T cells partly alleviated treatment’s efficacy. The expression of genes belonging to various T cell activation pathways was enriched in tumor-infiltrating leukocytes, whereas genes associated with immuno-suppressive pathways were decreased, possibly resulting in modifications of leukocyte adhesion and motility. Finally, we developed a simple in vivo assay in humanized mice to directly demonstrate that HVEM expressed by the tumor is an immune checkpoint for T cell-mediated tumor control. Our results show that targeting HVEM is a promising strategy for prostate cancer immunotherapy.

Radiotherapy-Related Gene Signature in Prostate Cancer

“…Increased levels of circulating BTLA or its high expression on CD8+ and CD4+ T-cell subsets have been reported to associate with poor prognosis in many types of malignant diseases [ 48 , 49 , 50 , 51 ]. More specifically, it has been shown that the reduction of BTLA expression in tumor infiltrating lymphocytes (TILs), through targeting HVEM , might result in better tumor control in a humanized mouse model of PCa [ 52 ]. Moreover, IFNγ production by tumor-specific CD8+ T-cells in response to melanocytic antigens has been shown to be impeded via BTLA signaling [ 53 ].…”

DNA Methylation Modification Regulator-Mediated Molecular Clusters and Tumor Metabolic Characterization in Prostate Cancer

“…Immune therapy is the most widely used treatment for many cancers, and its effect is associated with the expression of checkpoint genes [ 35 ]. Although PCa is an immune desert tumor, some studies have suggested the usefulness of immunotherapy for PCa [ 36 , 37 ]. Therefore, we compared the expression levels of checkpoint genes between the two groups.…”

Herpesvirus entry mediator on T cells as a protective factor for myasthenia gravis: A Mendelian randomization study

“…Interestingly, the third protective trait is the higher HVEM expression on various T-cell subtypes. HVEM, which belongs to the tumor necrosis factor receptor (TNFR) superfamily, has been recognized as a novel immune checkpoint in recent years ( 33 ). HVEM is expressed primarily on immune cells and functions as a ligand to activate the B- and T-lymphocyte attenuator (BTLA) on other immune cells ( 34 ).…”