Abstract
Simple SummaryCurrent immune checkpoint inhibitors have shown limitations for immunotherapy of prostate cancer. Thus, it is crucial to investigate other immune checkpoints to prevent disease progression in patients with prostate cancer. Here, we first show that the HVEM/BTLA immune checkpoint is associated with disease progression in patients. We then show that immunotherapy aimed at targeting HVEM reduced tumor growth twofold in vivo in a humanized mouse model of the pathology. The mode of action of the therapy was dependent on CD8+ T cells and is associated with improved T cell activation and reduced exhaustion. Finally, we demonstrated that HVEM expressed by the tumor negatively regulated the anti-tumor immune response. Our results indicate that targeting HVEM might be an attractive option for patients with prostate cancer.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.
Highlights
Immune escape by tumors is considered a hallmark of cancer [1]
Analysis of TCGA (The Cancer Genome Atlas) revealed that herpes virus entry mediator (HVEM) mRNA was expressed at high levels in the Prostate Adenocarcinoma (PRAD) (PRostate ADenocarcinomas) dataset and higher levels in primary tumors than in patient-matched normal tissues (Figure 1A)
For patients with Gleason scores of 6 or 7, above-median expression of HVEM was associated with a lower progression-free interval (PFI) over 5 years, whereas this was not observed for B and T lymphocyte attenuator (BTLA) (Figure 1C)
Summary
Immune escape by tumors is considered a hallmark of cancer [1]. Many immune mechanisms may explain the loss of tumor control, including defective MHC function and expression, recruitment of suppressive immune cells, and expression of co-inhibitory receptors such as PD-L1 [2]. The success of immune checkpoint inhibitors (ICI) remains partial as many patients fail to respond. This is relevant for prostate cancer (PCa), the second deadliest cancer in the industrialized world and for which numerous clinical trials using ICI monotherapy have been disappointing [4]. Limited tumor infiltrates (cold tumors) or low expression of the targeted molecule may explain the relative inefficiency of ICI [5,6]. To overcome these limitations, other pathways that might be involved in immune escape must be investigated as these could complement actual therapies
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