The HVEM network: new directions in targeting novel costimulatory/co-inhibitory molecules for cancer therapy

doi:10.1016/j.coph.2012.03.001

Current Opinion in Pharmacology

Volume 12, Issue 4, August 2012, Pages 478-485

https://doi.org/10.1016/j.coph.2012.03.001 Get rights and content

The regulation of the immune system is controlled by many cell surface receptors. A prominent representative is the ‘molecular switch’ HVEM (herpes virus entry mediator) that can activate either proinflammatory or inhibitory signaling pathways. HVEM ligands belong to two distinct families: the TNF-related cytokines LIGHT and lymphotoxin-α, and the Ig-related membrane proteins BTLA and CD160. HVEM and its ligands have been involved in the pathogenesis of various autoimmune and inflammatory diseases, but recent reports indicate that this network may also be involved in tumor progression and resistance to immune response. Here we summarize the recent advances made regarding the knowledge on HVEM and its ligands in cancer cells, and their potential roles in tumor progression and escape to immune responses. Blockade or enhancement of these pathways may help improving cancer therapy.

Highlights

► HVEM has five distinct ligands: LIGHT and LTα in the TNF family and BTLA, CD160 and herpesvirus gD in the Ig family. ► HVEM and its ligands are involved in the pathogenesis of autoimmune, inflammatory and neoplastic diseases. ► Recently described alterations of the HVEM network in tumor cells and microenvironment are discussed. ► Models for targeting these co-signaling molecules in cancer therapy are proposed.

Introduction

Co-signaling molecules include positive and negative receptors that allow regulation and fine tuning of the immune response. They consist of two superfamilies, classified based on their structure: the tumor necrosis factor receptor (TNFR) family characterized by cystein-rich domains (CRDs) in the extracellular portion, and the immunoglobulin (Ig) superfamily, or ‘CD28 and B7 family’, whose members contain Ig-variable-like extracellular domains. The TNFR superfamily comprises important players in costimulation and coinhibition, including 4-1BB, OX40, CD27, CD40 and HVEM. Concerning the Ig superfamily, apart from CD28 and ICOS that deliver co-stimulatory signals to T cells, other members of this family are involved in inhibiting or attenuating TCR-mediated activation. These co-inhibitory Ig members include CTLA-4, BTLA, PD1, and the recently discovered molecule CD160.

Here we focus on members of these families that attracted much attention during these past few years: the TNF receptor HVEM (herpes virus entry mediator), a molecular switch between proinflammatory and inhibitory signaling and the HVEM ligands, which are LIGHT (TNFSF14, lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus (HSV) glycoprotein D for HVEM, a receptor expressed by T lymphocytes), BTLA (B and T lymphocyte attenuator) and CD160. Given the importance of HVEM and its ligands in the physiopathology of immune regulation, it is now clear that the dysregulation of this network contributes to various diseases. Many reviews have highlighted the interest of manipulating these pathways in the context of autoimmunity and transplantation [1, 2•, 3•]. Recent studies of outstanding interest have also described abnormal expression of these co-stimulatory molecules in tumor cells [4•, 5•, 6••]. Moreover, clinical trials targeting members of these families, the co-inhibitory Ig molecules CTLA-4 and PD-1 (programmed death-1), have already given promising results in patients with melanoma, renal cell and prostate carcinoma, and non-Hodgkin's lymphoma [7]. In the same way, there is clear interest in evaluating the potential role of HVEM and its ligands in cancer therapy.

In this review we focus on (i) the expression patterns and function of HVEM and its ligands on normal tissues, (ii) the expression of these molecules in tumor cells and their involvement in tumor development and resistance to cancer, (iii) and the possible exploitation of these pathways for novel therapies using antibodies or recombinant proteins.

Section snippets

TNF-related and unconventional ligands

HVEM, first discovered as the entry route for HSV has the particularity to connect the two superfamilies. In general, receptor molecules of the Ig and TNF superfamilies interact with ligands within the Ig and TNF superfamilies, respectively, but not outside of their family. HVEM is different, as it interacts with the viral gD protein and the TNF-related cytokines: LIGHT and lymphotoxin-α (LTα) [8]. More surprisingly HVEM was found to interact with two members of the Ig superfamily: BTLA and

Expression patterns in normal cells

Analysis of the HVEM network and the functional outcome of HVEM engagement with its ligands is complicated by the widespread and regulated expression of BTLA, CD160, and LIGHT (Table 1).

HVEM is widely expressed on peripheral T and B cells, and is modulated during the lymphocyte activation: HVEM is strongly present on resting T cells, downregulated upon T cell activation and then re-expressed as the T cells return to a more resting state. HVEM expression is high in naïve and memory B cells, but

Expression patterns in cancers

Recently, some groups have reported abnormal expression of HVEM and its ligands in tumor cells or their microenvironment (Table 1).

Therapeutic perspectives

In the fields of autoimmunity, cell therapy and transplantation, there is great potential for the development of antibody-based and recombinant protein-based therapies to interfere with the stimulatory HVEM/LIGHT pathway and the inhibitory HVEM/BTLA/CD160 pathways. In autoimmunity and transplantation, one needs to attenuate undesirable T cell responses against self-antigens and alloantigens, respectively. In the context of anti-tumor therapy, the goal is to enhance anti-tumor immune responses.

Conclusions

The co-signaling molecules are crucial for regulating and maintaining efficient immune responses. Dysfunctions of the LIGHT-HVEM and BTLA-HVEM pathways are probably implied in the pathogenesis of various autoimmune and inflammatory diseases [28^•]. Dysregulations of this fine-tuned network are certainly also involved in neoplastic diseases.

The complexity of the HVEM network and the binding sites of the different ligands have to be considered for the development of specific antagonistic or

Conflict of interest

The authors declare no conflict of interest.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

References (38)

C.F. Ware
Targeting lymphocyte activation through the lymphotoxin and LIGHT pathways
Immunol Rev
(2008)
T. Duhen et al.
LIGHT costimulates CD40 triggering and induces immunoglobulin secretion; a novel key partner in T cell-dependent B cell terminal differentiation
Eur J Immunol
(2004)
M. Croft
The evolving crosstalk between co-stimulatory and co-inhibitory receptors: HVEM-BTLA
Trends Immunol
(2005)
P. Le Bouteiller et al.
Engagement of CD160 receptor by HLA-C is a triggering mechanism used by circulating natural killer (NK) cells to mediate cytotoxicity
Proc Natl Acad Sci USA
(2002)
R.T. Costello et al.
Stimulation of non-Hodgkin's lymphoma via HVEM: an alternate and safe way to increase Fas-induced apoptosis and improve tumor immunogenicity
Leukemia
(2003)
G. Cai et al.
The CD160, BTLA, LIGHT/HVEM pathway: a bidirectional switch regulating T-cell activation
Immunol Rev
(2009)
M.W. Steinberg et al.
The signaling networks of the herpesvirus entry mediator (TNFRSF14) in immune regulation
Immunol Rev
(2011)
M.L. del Rio et al.
HVEM/LIGHT/BTLA/CD160 cosignaling pathways as targets for immune regulation
J Leukoc Biol
(2010)
H. M’Hidi et al.
High expression of the inhibitory receptor BTLA in T-follicular helper cells and in B-cell small lymphocytic lymphoma/chronic lymphocytic leukemia
Am J Clin Pathol
(2009)
T.W. Farren et al.
Differential and tumor-specific expression of CD160 in B-cell malignancies
Blood
(2011)

L. Derre et al.

BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination

J Clin Invest

(2010)

W.J. Lesterhuis et al.

Cancer immunotherapy – revisited

Nat Rev Drug Discov

(2011)

T.L. Murphy et al.

Slow down and survive: enigmatic immunoregulation by BTLA and HVEM

Annu Rev Immunol

(2010)

J.L. Bodmer et al.

The molecular architecture of the TNF superfamily

Trends Biochem Sci

(2002)

J.R. Sedy et al.

B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator

Nat Immunol

(2005)

L.C. Gonzalez et al.

A coreceptor interaction between the CD28 and TNF receptor family members B and T lymphocyte attenuator and herpesvirus entry mediator

Proc Natl Acad Sci USA

(2005)

D.M. Compaan et al.

Attenuating lymphocyte activity: the crystal structure of the BTLA-HVEM complex

J Biol Chem

(2005)

G. Cai et al.

CD160 inhibits activation of human CD4+ T cells through interaction with herpesvirus entry mediator

Nat Immunol

(2008)

C.F. Ware et al.

TNF Superfamily Networks: bidirectional and interference pathways of the herpesvirus entry mediator (TNFSF14)

Curr Opin Immunol

(2011)

Cited by (56)

MIF promotes Th17 cell differentiation in Hashimoto's thyroiditis by binding HVEM and activating NF-κB signaling pathway
2023, International Immunopharmacology
Hashimoto's thyroiditis is a typical thyroid autoimmune disease and Th17 cells are crucial in its development. In recent years, MIF (Macrophage Migration Inhibitory Factor) has been found to promote the secretion of IL-17A and the production and differentiation of Th17 cells. However, the specific mechanism of it remains unclear. Here, we found that the expression of MIF, IL-17A and HVEM (Herpes Virus Entry Mediator) were up-regulated in HT patients. The proportion of Th17 cells in peripheral blood mononuclear cells was positively correlated with the serum MIF protein level. We further found that the expression of HVEM and the phosphorylation level of NF-κB in peripheral blood mononuclear cells of HT patients were significantly increased. Therefore, we speculated that MIF promotes Th17 cell differentiation through HVEM and NF-κB signaling pathways. Further mechanism studies showed that MIF could directly bind to HVEM, and the stimulation of rhMIF in vitro could increase the expression of HVEM and activate NF-κB signaling pathways to promote Th17 cell differentiation. After blocking HVEM with HVEM antibody, the effect of MIF on Th17 cell differentiation disappeared. The results above show that the differentiation of Th17 cells is promoted by MIF combined with HVEM through NF-κB signaling pathways. Our research provides a new theory to the regulation mechanism of Th17 cell differentiation and gives hint to new potential therapeutic targets for HT.
Adapting to the world: The determination and plasticity of T follicular helper cells
2022, Journal of Allergy and Clinical Immunology
Antibodies are crucial in host defenses as well as in allergic diseases. T follicular helper (T_FH) cells play essential roles in germinal center reactions by facilitating B-cell differentiation and immunoglobulin affinity maturation and isotype switching. Although T_FH cells have a unique gene transcription program and regulatory network, recently there has been increasing evidence of T_FH cell plasticity, with some T_FH cells expressing genes typically related to other types of effector T cells associated with different types of Ig subclasses and in the context of different pathogen infections and health conditions. Here, we review the plasticity of T_FH cells in various types of immune responses. We also point out the important implications of T_FH plasticity in understanding and treating human diseases, including allergy.
Role of BTLA/HVEM network in development of gastric cancer
2022, Human Immunology
The immunopathological mechanism underlying intestinal metaplasia and gastric cancer remain incompletely understood. Regarding the role of B- and T-lymphocyte attenuator (BTLA) / herpesvirus entry mediator (HVEM) in tumorigenesis, this research was conducted to determine the BTLA/HVEM expression in development of gastric cancer. Gastric biopsy and peripheral blood was drawn from 32 non-ulcer dyspepsia (NUD) as control group, 19 intestinal metaplasia (IM), and 63 gastric cancer (GC). BTLA/HVEM expression were analyzed by immunohistochemistry and quantitative real-time polymerase chain reaction. Soluble HVEM (sHVEM) and anti-Helicobacter pylori IgG antibody were assessed by ELISA. Our result showed that BTLA mRNA and protein were significantly increased in advanced stages of gastric cancer. HVEM was higher only at the protein level in the GC group. The sHVEM concentration was also higher in the GC group than in the NUD groups. In addition, we observed H. pylori-positive samples had a lower H-score of HVEM than H. pylori-negative ones. These results suggest that BTLA/HVEM/sHVEM inhibitory pathway is involved in immune regulation and progression of gastric cancer. Therefore, this inhibitory pathway might be a therapeutic target to further immunotherapy of gastric cancer.
Herpes Virus Entry Mediator (HVEM): A Novel Potential Mediator of Trauma-Induced Immunosuppression
2020, Journal of Surgical Research
Citation Excerpt :
It is speculated that it is the nonspecific nature of these therapeutic strategies that have failed to produce the desired clinical outcomes, and many have called for a more focused, pathway-based approach to modulating immune effects of trauma.28 However, immune checkpoint directed therapy has shown tremendous potential in a range of medical conditions, most notably in mediating the immune response to malignancies.39,40 Checkpoint proteins such as HVEM, BTLA, and PD-1 are capable of regulating either an immunosuppressive or immunostimulatory role depending of the specific stressor.
Herpes virus entry mediator (HVEM) is a coinhibitory molecule which can both stimulate and inhibit host immune responses. Altered expression of HVEM and its ligands is associated with increased nosocomial infections in septic patients. We hypothesize critically ill trauma patients will display increased lymphocyte HVEM expression and that such alteration is predictive of infectious events.
Trauma patients prospectively enrolled from the ICU were compared with healthy controls. Leukocytes were isolated from whole blood, stained for CD3 (lymphocytes) and HVEM, and evaluated by flow cytometry. Charts were reviewed for injuries sustained, APACHE II score, hospital course, and secondary infections.
Trauma patients (n = 31) were older (46.7 ± 2.4 versus 36.8 ± 2.1 y; P = 0.03) than healthy controls (n = 10), but matched for male sex (74% versus 60%; P = 0.4). Trauma patients had higher presenting WBC (13.9 ± 1.3 versus 5.6 ± 0.5 × 10⁶/mL; P = 0.002), lower percentage of CD3⁺ lymphocytes (7.5% ± 0.8 versus 22.5% ± 0.9; P < 0.001), but significantly greater expression of HVEM⁺/CD3⁺ lymphocytes (89.6% ± 1.46 versus 67.3% ± 1.7; P < 0.001). Among trauma patients, secondary infection during the hospitalization was associated with higher APACHE II scores (20.6 ± 1.6 versus 13.6 ± 1.4; P = 0.03) and markedly lower CD3⁺ lymphocyte HVEM expression (75% ± 2.6 versus 93% ± 0.7; P < 0.01).
HVEM expression on CD3⁺ cells increases after trauma. Patients developing secondary infections have less circulating HVEM⁺CD3⁺. This implies HVEM signaling in lymphocytes plays a role in maintaining host defense to infection in after trauma. HVEM expression may represent a marker of infectious risk as well as a potential therapeutic target, modulating immune responses to trauma.
Expression of PD1 and BTLA on the CD8<sup>+</sup> T Cell and γδT Cell Subsets in Peripheral Blood of Non-Small Cell Lung Cancer Patients
2019, Chinese Medical Sciences Journal
To investigate the expression and regulation of programmed cell death protein 1 (PD1), B lymphocyte and T lymphocyte attenuator (BTLA) in peripheral blood of patients with non-small cell lung cancer (NSCLC); to examine the correlation of the mRNA levels between PD and BTLA in NSCLC.
Flow cytometry was used to detect the expression of PD1 and BTLA on the surfaces of CD8⁺T cells and γδ⁺ T cells in the peripheral blood samples collected from 32 in-patients with stage IV NSCLC and 30 healthy individuals. We compared the expression of PD1 and BTLA on the surfaces of γδ⁺ T cells in the NSCLC patients with bone metastasis before and after the treatment of zoledronic acid. The correlations of PD1 and BTLA, as well as their ligands were analyzed using Pearson correlation analysis with the cBioPortal data platform.
The frequency of PD1 on the surfaces of CD8⁺ T cells was significantly higher than that of the γδT cells in both healthy controls (t=2.324, P = 0.024) and NSCLC patients (t = 2.498, P = 0.015). The frequency of PD1 on CD8⁺ T cells, rather than on γδ⁺ T cells, was significantly upregulated in advanced NSCLC patients compared with that in healthy controls (t = 4.829, P< 0.001). The PD1⁺ BTLA γδT cells of the healthy controls were significantly lower than that of the NSCLC patients (t = 2.422, P = 0.0185). No differences in percentage of PD1⁺γδ⁺ and BTLA⁺γδ⁺ T cells were observed in 7 NSCLC patients with bone metastasis before and after zoledronic acid treatment. PD1 was positively correlated with BTLA in both lung adenocarcinoma (r = 0.54; P< 0.05) and lung squamous cell carcinoma (r = 0.78; P< 0.05).
The upregulation of co-inhibitory molecules occurs on the surfaces of both CD8⁺T cells and γδT cells in advanced NSCLC, suggesting that these molecules were involved in regulating the inactivation of CD8⁺T cells and γδ⁺T cells, immune escape and tumor invasion.
Resveratrol antagonizes thyroid hormone-induced expression of checkpoint and proliferative genes in oral cancer cells
2019, Journal of Dental Sciences
Dysregulation of cell cycle checkpoint control may lead to the independence of growth regulating signals. Checkpoint protein such as the PD-1/PD-L1 immune checkpoint involving tumor cells and host immune defense lymphocytes is a well-studied therapeutic target in oncology. Acting at a cell surface receptor on plasma membrane integrin αvβ3, thyroxine stimulates intracellular accumulation of PD-L1 in cancer cells. Although resveratrol also binds to integrin αvβ3, it reduces PD-L1 expression.
In current studies, we investigated the roles of resveratrol and thyroxine in regulating expression of proliferation-related genes and checkpoint genes, PD-L1, BTLA in two oral cancer cell lines.
Thyroxine suppressed the expression of pro-apoptotic BAD but induced proliferative CCND1 expression in SSC-25 cells and OEC-M1 cells. It activated expression of PD-L1 and BTLA in both cell lines. On the other hand, resveratrol suppressed the expression of all. Alternatively, it activated BAD expression. Thus thyroxine induces checkpoint gene expression which may promote proliferation in cancer cells. Alternatively, resveratrol reverses the stimulatory effects of thyroid hormone to induce anti-proliferation.
These findings provide new insights into the antagonizing effect of resveratrol on the thyroxine-induced expression of checkpoint genes and proliferative genes in oral cancers.

View all citing articles on Scopus

View full text

The HVEM network: new directions in targeting novel costimulatory/co-inhibitory molecules for cancer therapy

Highlights

Introduction

Section snippets

TNF-related and unconventional ligands

Expression patterns in normal cells

Expression patterns in cancers

Therapeutic perspectives

Conclusions

Conflict of interest

References and recommended reading

Immunol Rev

Eur J Immunol

Trends Immunol

Proc Natl Acad Sci USA

Leukemia

The CD160, BTLA, LIGHT/HVEM pathway: a bidirectional switch regulating T-cell activation

Immunol Rev

The signaling networks of the herpesvirus entry mediator (TNFRSF14) in immune regulation

Immunol Rev

HVEM/LIGHT/BTLA/CD160 cosignaling pathways as targets for immune regulation

J Leukoc Biol

High expression of the inhibitory receptor BTLA in T-follicular helper cells and in B-cell small lymphocytic lymphoma/chronic lymphocytic leukemia

Am J Clin Pathol

Differential and tumor-specific expression of CD160 in B-cell malignancies

Blood

BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination

J Clin Invest

Cancer immunotherapy – revisited

Nat Rev Drug Discov

Slow down and survive: enigmatic immunoregulation by BTLA and HVEM

Annu Rev Immunol

The molecular architecture of the TNF superfamily

Trends Biochem Sci

B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator

Nat Immunol

A coreceptor interaction between the CD28 and TNF receptor family members B and T lymphocyte attenuator and herpesvirus entry mediator

Proc Natl Acad Sci USA

Attenuating lymphocyte activity: the crystal structure of the BTLA-HVEM complex

J Biol Chem

CD160 inhibits activation of human CD4+ T cells through interaction with herpesvirus entry mediator

Nat Immunol

TNF Superfamily Networks: bidirectional and interference pathways of the herpesvirus entry mediator (TNFSF14)

Curr Opin Immunol