Preprint Article Version 2 Preserved in Portico This version is not peer-reviewed

HVEM is a Novel Immune Checkpoint for Prostate Cancer Immunotherapy in Humanized Mice

Version 1 : Received: 12 May 2021 / Approved: 13 May 2021 / Online: 13 May 2021 (13:55:38 CEST)
Version 2 : Received: 8 June 2021 / Approved: 9 June 2021 / Online: 9 June 2021 (11:26:57 CEST)

A peer-reviewed article of this Preprint also exists.

Aubert, N.; Brunel, S.; Olive, D.; Marodon, G. Blockade of HVEM for Prostate Cancer Immunotherapy in Humanized Mice. Cancers 2021, 13, 3009. Aubert, N.; Brunel, S.; Olive, D.; Marodon, G. Blockade of HVEM for Prostate Cancer Immunotherapy in Humanized Mice. Cancers 2021, 13, 3009.


The Herpes Virus Entry Mediator (HVEM) delivers a negative signal to T cells mainly through the B and T Lymphocyte Attenuator (BTLA) molecule and thus, could represent a novel immune checkpoint during an anti-tumor immune response. A formal demonstration that HVEM can be targeted for cancer immunotherapy is however still lacking. Here, we first show that HVEM and BTLA were associated to a worse prognosis in patients with prostate adenocarcinomas, indicating a detrimental role for this pair of molecule during prostate cancer progression. We then show that a monoclonal antibody to human HVEM significantly impacted the growth of a prostate cancer cell line in immuno-compromised NOD.SCID.gc-null mice reconstituted with human T cells. Using CRISPR/Cas9, we showed that HVEM expression by the tumor was mandatory to observe the therapeutic effect. Mechanistically, tumor control was dependent on CD8+ T cells and was associated to an increase in the proliferation and number of tumor-infiltrating leukocytes. Accordingly, the expression of genes belonging to various T cell activation pathways were 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 was an immune checkpoint for T-cell mediated tumor control. Our results show that targeting HVEM is a promising strategy for prostate cancer immunotherapy.


immune checkpoint; HVEM; BTLA; monoclonal antibody; cancer immunotherapy; humanized mice; prostate cancer


Biology and Life Sciences, Biochemistry and Molecular Biology

Comments (1)

Comment 1
Received: 9 June 2021
Commenter: gilles Marodon
Commenter's Conflict of Interests: Author
Comment: New data and new supplemental figures have been added. The results and discussion sections have been modified accordingly.
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