A Review Of The Immune System Biology Essay



The immune system, or lymphatic system, is a complex arrangement of structures and processes that aid in the elimination of microbes or pathogens. Monitoring for invading microbes is the function of the lymphatic system, in addition to the exchange of cells and fluids between the blood and lymphatic vessels (2). It defends the body against microbes, such as bacteria, viruses, or parasites that cause disease and other pathologies (2). Microbes are quite diverse and can infect hosts using many pathways and different microbes are eliminated by different parts of the immune system (2).

The immune system is essential in maintaining homeostasis and good health. When this system is threatened the body sends a pathogenic invasion signal for the immune cells to step in to release chemicals that effectively direct the immune cells to the site of infection

Immediately upon recognizing invading cells or microbes, the immune system produces secretions which contain immune cells that inactivate the foreign entities (2). The function of the immune system is to act as a protective healing force against an invading presence that threatens the health of its host. There are two major components to the immune system: innate immunity and adaptive immunity. Innate immunity is found in virtually all life forms, is non-specific, and exposure leads to an instant maximum response (26, 27). Adaptive immunity is only found in vertebrates, and its antigen and pathogen specific response is not instantaneous (26, 27).

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The Lymph nodes are important organs of this system, acting as the site of immune cell recruitment and antigen presentation (2). Antigen presentation occurs when a phagocyte, a white blood cell that specializes in the absorption of microbes, engulfs bacteria and the bacterial antigens are displayed in Major Histocompatibility Complex (MHC) molecules on the surface of the phagocyte. MHC molecules are proteins that are recognized by T-cells when the body is trying to distinguish its cells from unfamiliar cells, and in the fight to eliminate pathogens, it is imperative that the body can recognize its own cells versus foreign cells (2). The phagocyte then presents antigens to Helper T-cells (CD4+). Activated Helper T-cells can then stimulate B cells to produce antibodies or activates Cytotoxic T-cells (CD8+) (2). For example, given most bacteria live in the junction between cells, they are attacked quickly by antibodies via attachment. After attachment occurs, antibodies send signals to complement proteins and phagocytic cells to obliterate the microbe. In the case of viruses, the host cell displays viral antigens within its MHC which alerts Cytotoxic T- lymphocytes of invasion and induces an immune response (2).

B cells, T-cells, and phagocytes are major immune cells that are derived from bone marrow. B cells and T-cells are the two main types of lymphocytes. B cells secrete antibodies into the body's fluids and are programmed to make an antibody with a single specificity (2). Once a B cell encounters its antigen, it is activated and forms numerous plasma cells. These plasma cells are tiny factories that continuously produce and secrete antibodies. Plasma cells can manufacture up to millions of identical antibody molecules and then release them into the blood stream (2). T-cells direct and regulate immune responses to other cells or directly attack infected cells (2). There are two types of T-cells, Helper T-cells and Killer T-cells. Killer T-cells, also known as Cytotoxic T lymphocytes (CD8+), are responsible for a direct attack on abnormal or infected cells that they encounter. One of the main targets of Cytotoxic T lymphocytes (specifically tumor-infiltrating lymphocytes) are cancer cells. CTLs can destroy these tumor targets via two cellular mechanisms. The first, involves the discharge of perforin proteins and granzymes (serine proteases) released from these cells, resulting in lysis of the target cell. The second mechanism involves direct ligation of Fas ligand (FasL) on these activated T-cells and the Fas receptor on the tumor cell surface, resulting in apoptosis of the tumor target (4).

Cancer Immunology

Cancer, a malignant neoplasm, is a crippling disease responsible for the second largest cause of death in the country. A majority of cancer cases in humans are solid tumors that developed from varying types of epithelial cells, forming carcinomas (1). Cancer cells are usually caused by mutations in genes, generally characterized by uninhibited growth, invasion of surrounding tissues and metastasis of cells to other parts of the body (24). Although immune cells can respond to foreign growths in the body as an invasion of the homeostasis, they often do not respond to tumors at all, or do so inefficiently (25). Possible mechanisms for this insufficient immune response in tumor cells could be immune suppression via no co-stimulation or inhibitory stromal interactions.

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The cells of tumor masses can include normal cells in and around the tumor, collectively called tumor stroma. Stroma is critical for allowing immunologic attack of cancer cells, and is essential for maintenance of tumor growth, vasculature supply, and the determination of tumorigenicity of cancer cells (1, 15). Stroma is composed mainly of fibroblast cells, which can regulate immune cells, gaining access to tumors. It can either inhibit the access of T-cells into the tumor, or conversely recruit immune cells into the tumor and allow the elimination of cancer cells (1). Furthermore, stroma has been shown to prevent T-cell priming and proliferation in tumor sites, which is the negative effective researchers try to avoid in cancer immunotherapy (6).

Another hypothesis behind why the immune system does not eliminate tumors is that perhaps, tumors lack the co-stimulatory molecules necessary to successfully induce and uphold T-cells (1). The T-cell antigen receptor (TCR) is the first signal responsible for initiating preliminary activation of the cell. It acts in an antigen specific way that assists in the regulation of several aspects of cellular responses (3). This first signal is initiated upon interaction between the TCR on CD8 cells and class I MHC molecules on the target tumor. The second signal involves CD28 on the T-cell binding to B7-1 on the target cell, which provides the necessary co-stimulation for proper T-cell activation. This second signal is stabilized by stimulating T-cells with cytokines. This positive example of T-cell proliferation is the precise immune response needed to effectively treat cancer (22).

Since T-cells respond to foreign antigens via peptides bound to self MHC molecules on the surface of other cells, the T-cell immune response is controlled and maintained on two levels. The first is via co-stimulatory or co-inhibitory proteins expressed on their surfaces and the second is via a range of ligands displayed on the antigen-presenting cell (3). In the absence of co-signaling pathways, T-cell activation is not upheld (5). It has since been determined that some recognized tumors do in fact express two co-stimulatory molecules: B7-1 and CD48 (1). B7-1 is the natural ligand for the T-cell antigen CD28 and mediator of B and T-cell adhesion. CD28 is present on all CD4+ and most CD8+ T-cells. Binding of B7-1 induces a co-stimulatory signal that leads to the upregulation of lymphokines, or cytokines produced by lymphocytes. CD48 is a protein involved in T-cell activation, expressed by these three cell types: lymphocytes, dendritic cells and macrophages (1). Signaling through these co-stimulatory molecules is not always sufficient to elicit a successful immune response that is strong enough to eliminate tumors. This has prompted investigators to evaluate other co-stimulatory molecules capable of inducing strong anti-tumor T cell responses and thus we look at LIGHT.


LIGHT is a powerful, CD28-independent, protein essential in early T cell priming and development. LIGHT, also known as TNFSF14, is a lymphotoxin-β (LTβ)-related member of the Tumor necrosis factor (TNF) Superfamily (1, 5, 7, 12). It is a type II membrane protein that is present on the surface of immature dendritic cells, as well as activated lymphocytes, such as T, B, and Natural Killer Cells, and it appears to be essential in regulating T-cell inflammatory responses (18, 21).

The search for completely effective cancer immunotherapy treatments is on the rise and some pathways, including LIGHT, as well as other co-stimulatory receptors, are being assessed and altered for cancer therapy purposes. The structure and function of the receptor-ligand interactions in this cytokine family are being reviewed, to better understand how they can be positively manipulated for therapeutic purposes. Members of this TNFSF cytokine family serve as an elaborate extracellular communication complex, consisting of ligands and receptors that regulate numerous stages of development (7). Examples of other ligand-receptor pairs in this family are: FasL-Fas, OX-40 Ligand-OX-40, CD27 ligand-CD27, and TWEAK-TWEAK-R (5, 18, 28). Cytokines mediate important pathways necessary for immune response control, and this particular family of cytokines aid in various cellular life processes, such as growth, development, cell death, and T-cell co-stimulation (5). Examples of cytokines in this family are: B-cell activating factor (BAFF) and TNF-Related apoptosis inducing ligand (TRAIL) (28).

This family, along with its receptors, activates antigen-responding lymphocytes and essential interactive pathways vital for the regulation of immune response (5). This TNF family can be expressed in multiple cell types, such as Lymphoid cells and stromal cells, and have numerous receptors whose biological activity is exhibited through cell surface-receptor interactions (5). More specifically, the TNF superfamily is a regulator of T-cell activation dependent upon proper antigen signaling through the TCR (5).

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LIGHT has been shown to have two major effects that researchers believe could stimulate tumor elimination. First, is the ability of LIGHT to positively assist the immune system by decreasing the inhibitory abilities of stroma, and the second is by directly triggering apoptosis of tumor cells (6, 14). T-cell proliferation or differentiation, and even initiation of tumor cell death can be regulated by LIGHT depending on cell type expression and which receptor is engaged (20). LIGHT has three receptors: HVEM, LTβR and TR6 (Figure 2). These receptors bind LIGHT with a high affinity and their signaling pathways are cell-context specific. Inhibition of these various interactions between LIGHT and HVEM or LTβ receptors, have been shown to cause adverse effects on cells, such as loss of appropriate T-cell function, programmed cell death, and overall activation blockage (5).


Herpes Virus Entry Mediator (HVEM), one of the ligands for LIGHT, is a member of the Tumor Necrosis Factor Receptor Family (14). HVEM displays inducible expression on lymphocytes and is found in lymphocyte-rich organs, such as the thymus and spleen (7). It has high affinity for LIGHT and is displayed on B, T, epithelial, immature dendritic and natural killer cells (10, 18). In most cases, HVEM signals give anti-cell death or growth-initiating properties to cells (7). In studies using anti-HVEM antibodies with CD28 stimulated T-cells, a reduction in T-cell and cytokine production occurred, confirming the positive, stimulatory function of HVEM (7). Binding of LIGHT to HVEM on T-cells, results in co-stimulation and maintenance of T-cell activation, priming and development (18).

LIGHT and HVEM have been shown to act as co-stimulators of T-cells, with the mystery of the mechanism still being unraveled. This receptor-ligand pair transduces proper secondary signals in order to attain accurate T-cell establishment (7). Following the use of anti-HVEM antibodies on CD3/CD28 stimulated T cells, a reduction of T-cell propagation and cytokine production occurred. This data provided some indication that HVEM signaling was a stimulator of T-cells (14). As a pair, LIGHT-HVEM co-stimulation generate cytokines, such as Interferon-γ (IFN-γ) and Granulocyte Macrophage- colony stimulating factor (GM-CSF) that aid in immune response to cancer by pushing towards cell mediated immunity (7).

B and T lymphocyte attenuator (BTLA) can join HVEM and LIGHT (Figure 1) to form a multifaceted regulatory network. BTLA is a type I transmembrane, co-inhibitory glycoprotein whose expression is induced during T-cell activation and differentiation (22). BTLA shares the HVEM ligand with LIGHT, and has been shown to be present on the surface of T-helper 1 (Th1) cells. BTLA binding has been shown to inactivate B and T lymphocytes (3). HVEM can concurrently bind LIGHT and BTLA, without inhibiting each other and producing a monomeric structure between HVEM and BTLA. HVEM acts as a molecular control between immune stimulatory and inhibitory signaling (5).

The ligation of BTLA and HVEM is one of the first examples of co-stimulatory and co-inhibitory receptor crosslink, demonstrating the ability of BTLA to regulate T-cell activation via interaction with HVEM (22). Experiments using BTLA-deficient mice, suggests that specifically inhibiting BTLA alone induces CD8+ T-cell memory formation (22). Used as a combination by targeting various antigens to the BTLA-HVEM complex binding site, B and T-cell reactions to those antigens showed an usual increase in activation. This suggests BTLA acts as an agonist by activating HVEM signaling, with HVEM overriding the inhibitory properties of BTLA (8, 22).

Due to the structural similarities between ligands, it is thought that the connection between LIGHT and HVEM could promote the binding of BTLA to HVEM. To examine the regulatory network involving BTLA, HVEM, and LIGHT, researchers used 293T-cells transfected with HVEM and co-cultured with 293T-BTLA cells. All cells were co-cultured in the presence of soluble LIGHT. It was found that soluble LIGHT did in fact increase BTLA binding and activation. This indicated that LIGHT and BTLA could cooperatively enhance HVEM-signaling (8).


Lymphotoxin Beta Receptor (LTβR) is the second most prominent receptor that has a high affinity for LIGHT (14). It is a member of the tumor necrosis factor receptor (TNFR) family whose function was initially said to be in the development of secondary lymphoid tissues (4). The LTβR signaling pathway was later shown to be involved in other biological processes, such as the initiation of tumor cell death (4). LTβR is normally found in monocytes and stromal cells, unlike its counterpart HVEM, which is shown to be expressed in many lymphocyte cells. It serves as an indirect T-cell activator by regulating the differentiation of various cells, such as: stromal cells, mast cells, and macrophages and antigen-presenting dendritic cells.

LTβR protein has also been observed in various human tumor tissue lines from organs, such as the lung, larynx/pharynx, stomach and at the joining of the colon and rectum (4). Interestingly, LTβR has been shown to be a death receptor responsible for mediating the programmed cell death of various tumor cell lines (4).

Additional studies were performed to further understand the activities of HVEM versus LTβR signaling through LIGHT. Soluble forms of HVEM and LTβR were used to inactivate the ligands and further examine each pathway. The study found that of the two interactions, the LIGHT-HVEM pathway is the more direct co-signaling agent in T-cells, while LIGHT-LTβR was found to initiate tumor cell death (7, 14).


TR6, also known as decoy receptor 3 (DcR3), is another member of the TNFR family and is a soluble receptor for LIGHT (11, 13). TR6 is normally expressed in lung tissue, lymph nodes, spleen, endothelial cells and in some tumor cells (11, 13). On human T-cell lines, it has been shown to restrain CTL and cytokine activity (13). Previously, LIGHT ligation was thought to only alter the activity of the receiving cell and signal into T-cells which express HVEM or LTβR. It has now been found that the opposite can occur, and that the cell expressing LIGHT can also receive a signal, as is the case with TR6 (11).

Cancer Immunotherapy using LIGHT

Researchers have looked at the capability of LIGHT to aid the immune system in eliminating tumors using several mechanisms. Some of these mechanisms are: LIGHT's ability to directly trigger apoptosis of tumor cells, and LIGHT's ability to decrease the capacity of stroma to secrete proteins that inhibit recruitment of T-cells. Additionally, they looked at LIGHT's ability to directly co-stimulate T-cells, as well as, LIGHT's ability to induce NK cells.

Tumor Death by LIGHT

The exact role of LIGHT in anti-tumor immunity has been of interest since anti-tumor effects were first observed in a tumor model (9). In this particular model, Zhai et al. (9) used LIGHT expressed on complementary DNA (cDNA) and injected it into MDA-MB-231 human breast carcinoma cells. This in vivo study reported LIGHT-induced tumor cell cytotoxicity, while stimulating the secretion of the cytokine IFN-γ from activated PBL (9). These data suggest that LIGHT could initiate tumor cell death, while stimulating immune cell function.

Although the study reported positive cytotoxic effects administering LIGHT alone, Zhai et al. (9) were also interested in the involvement of LIGHT receptors in growth inhibition of cancer cells. Zhai et al. (9) hypothesized that tumor cell growth inhibition would produce better results in the presence of LIGHT receptors. To test this hypothesis, researchers used human prostate cancer cell lines normally expressing LTβR and transfected the cells with HVEM. It was demonstrated that soluble LIGHT-mediated growth inhibition of tumor cells was most effective when both HVEM and LTβR were expressed (9). These data suggest that LIGHT may control various biological reactions based on the expression of its receptors to the target cells (9).

LTβR has been shown to enhance pro-inflammatory responses, initiate the expression of adhesion molecules and stimulate apoptosis in various tumor cell lines (20, 23). In one study, Browning et al. (20) hypothesized that LTβR could induce cell death and growth inhibition in tumor cells. To test this hypothesis, anti-LTβR monoclonal antibodies were injected into two types of human colon adenocarcinoma cell lines, HT-29 and WiDR and cytotoxicity assessed. LTβR-specific antibodies directly increased tumor cell death and thus researchers concluded that LTβR could signal cell death, inducing cytotoxicity.

Similarly, Browning et al. (20) wanted to explore growth inhibition in WiDR cell lines of immunodeficient mice via the use of anti-LTβR antibodies. Cancer is a genetic mutation known to disrupt immune function. Due to this fact, immunodeficient mice are great models that researchers use to further understand tumor growth and immune system development. In this particular experiment, researchers wanted to assess whether or not LTβR could induce cell death alone, without the presence of T-cells, which required the use of immunocompromised mice. Researchers hypothesized that anti-LTβR antibodies would inhibit the growth WiDR cells. At the same time the mice were implanted with the antibodies intraperitoneally, the tumor cells were inoculated subcutaneously (20). Their hypothesis was supported when anti-LTβR antibodies produced moderate growth inhibition which resulted in seven out of sixteen mouse subjects completely tumor free (20). Anti-tumor immunity also proved to be enhanced by IFN-γ. These data suggest LTβR signaling could in fact induce cell death in these two particular tumor cell lines.

LIGHT complexes, are capable of inducing tumor cell apoptosis. Initial studies suggested that HVEM and LTβR could both be essential in LIGHT's ability to trigger apoptosis, although both lack the typical death domain (14). Due to the previous studies, Researchers were convinced they should look into LTβR ligating with LIGHT, to see if better tumor regression results could be established (4). Yang et al. (4) started by assessing LTβR's interaction with tumor-specific T lymphocytes and role in tumor regression. Researchers first implanted CMS4-met tumor cells, expressing Fas-mediated apoptosis inhibitor, into mice to produce lung metastasis (4). Three days after tumor implantation, CTLs were transferred into the mice. The CTLs exhibited tumor cell cytotoxicity and these data suggested they could mediate tumor elimination pathways. This data led Yang et al. to hypothesize that LTβR could be the receptor responsible for the CTL-mediated, Fas-independent and perforin-independent mechanisms. To test this hypothesis, researchers analyzed expression of LTβR in CMS4-met and 4T1 cell lines, and found LTβR to present on the surface (4). They also found the ligand LIGHT up-regulated in the activated CTLs. Subsequently, Yang et al. blocked the function of LTβR on the surface of these tumor cells lines using a LTβR-specific neutralizing antibody and stimulated CD8+ T-cells using anti-CD3 and CD28 antibodies. Then researchers measured the amount of tumor cell death and found that blockage of LTβR significantly decreased CTL-mediated cytotoxicity (4). These data suggest that tumor-specific CTLs perform anti-tumor cytotoxicity via LTβR, an anti-tumor effector mediator (4). Data now suggests that CTLs actually use three cellular mechanisms of CTL lysis, as opposed to two. The third mechanism shown to be a pathway mediated by LTβR (4).

Both HVEM and LTβR have been shown to interact with LIGHT and positively mediate tumor cell death of HT-29 human colon carcinoma cells (11). Consequently, Yu et al. (11) set out to determine what role the third LIGHT receptor, TR6, could also play in cell death of the same tumor line. First, researchers determined whether TR6 might act as an inhibitor to LIGHT interactions with HVEM and LTβR. Yu et al. used HT-29 cells inoculated with soluble LIGHT, IFN-γ, and either LTβR or TR6 in vitro. Researchers reported that TR6 significantly blocked tumor cell death and was shown to act as an inhibitor in LIGHT-generated tumor cell death, by way of hindering the interaction of HVEM and LIGHT (11).

LIGHT and Natural Killer Cells

The introduction of LIGHT expression into tumors can trigger the activation of numerous immune cells, positively resulting in tumor rejection (5, 9). Previous literature suggested that tumor cell death was caused by Natural Killer (NK) cells, which are a part of the immediate response known as innate immunity (21). Fan et al. (21) wanted to further examine what role NK cells played in LIGHT-mediated tumor rejection. Fan et al. (21) hypothesized that NK cells would increase LIGHT-mediated tumor rejection. To test this hypothesis, mice were treated in vivo with NK-depleting antibodies on varying days after/post Ag104Ld tumor implantation (21). Results showed that the loss of NK cells significantly improved tumor growth, thus suggesting NK cells as key players in LIGHT-mediated rejection and LIGHT as the co-stimulatory activator of these NK cells. Next, Ag104Ld LIGHT tumor cells were implanted into mice deficient of B, T, and NKT cells. All tumors found in the wild-type mice were rejected after twenty-two days, suggesting that NK cells alone were not sufficient to eliminate the tumors and could possibly need the aid of CD8+ T-cells (21).

To further examine the role of NK cells in tumor regression, Fan et al. (21) correlated increases in LIGHT-mediated tumor regression with accumulation of NK cells (21). Using NK and CD8+ T-cell deficient mice, researchers determined that neither NK cells nor CD8+ T-cells alone were substantial enough to completely reject tumor cell lines. However, Fan et al. (21) did report an increase in NK cells inside LIGHT transfected tumors, which in turn promoted further activation of CD8+ T-cells inside the tumor (21). After these results, researchers wanted to evaluate the direct interaction between NK cells and LIGHT. Fan et al. (21) used the same Ag104Ld LIGHT tumor cell line and co-cultured it with NK cells (21). Significant NK cell proliferation was shown in those NK cells inoculated with Ag104Ld LIGHT. Furthermore, these proliferating NK cells were able to stimulate an increase in CTL expansion. Ultimately, this study reported that up-regulating the expression of LIGHT in tumor cells may in fact help activate NK cells and subsequently CTLs, leading to tumor rejection (21). Fan et al. (21) now believe that NK cells stimulated by LIGHT could eradicate cells at the primary tumor site, while activation and expansion of CTLs could promote elimination at distal tumor sites (21).

Recruitment and Co-Stimulation of Immune Cells by LIGHT

Activation of LIGHT up-regulates the translation of cytokines and chemokines (IFN-γ, Interleukin-8 and Monocyte Chemotactic Protein-1) on various cells, such as endothelial cells, and the expression of adhesion molecules in tumor tissue cell lines (12). Chemokines are cytokines secreted by cells that can activate chemotaxis in other cells (1, 26). Some chemokines stimulate immune cells to migrate to a site of infection and destroy a particular pathogen. As a result, chemokines could recruit immature T-cells into the tumor and then co-stimulation via LIGHT could develop them within the tumor site (6). LIGHT transfected Ag104Ld tumor cell lines were used to test the hypothesis in vivo. Yu P et al. (6) wanted to analyze the effectiveness of LIGHT in tumor elimination and initiating immune responses, and found that depletion of CD8+ T-cells led to an increase in Ag104Ld LIGHT tumor cell growth. This data suggests that CD8+ T cell co-stimulation is essential for LIGHT-mediated tumor regression (6). Researchers also saw activation of circulating T-cells led to rejection of Ag104Ld tumor cell lines locally and at distal sites (6). Yu P et al. (6) also hypothesized that LIGHT could stimulate LTβR on stromal cells and induce chemokine production. Tumor tissue was collected from mice ten to fourteen days after inoculation with Ag104Ld tumor cells (6). Researchers reported chemokine (CCL21 and MAdCAM-1) production and secretion from stromal cells mediated by LTβR, which created an environment that attracted the recruitment of T-cells. This created an upregulation of T-cells into the tumor, suggesting enhanced chemotaxis (6).

Tamada et al. (14) sought to analyze the role of increased LIGHT co-stimulation in cell-mediated immune response. In this research study, P815 tumor cells were implanted into mice, and tumors developed within a week (14). Subsequently, repeat injections of pmLIGHT plasmid were inserted into the newly developed tumors and effects on tumor regression assessed. One week following the final injection of pmLIGHT, spleen cells were stimulated, cultured and demonstrated increased CTL activity reacting with P815 tumor antigens in vitro (14). The CTLs successfully lysed P815 cells in large amounts, confirming CTLs were specific for this particular tumor cell antigen and showing successful CTL response via LIGHT co-stimulation. Repeat injections over a three week time frame showed regression of all tumors in mice treated with pmLIGHT plasmid. These data suggest pmLIGHT in P815 tumor cells elicit tumor cell death, while utilizing a T-cell dependent mechanism.

In preceding studies, HVEM's regulation of T-cell activity has been of interest to researchers. In one particular study, Harrop et al. (16) hypothesized that the HVEM Ligand (HVEM-L) and cytokines could share similar cell activities. To test this theory, researchers assessed the ability of HVEM-L to reduce tumor cell growth. HT-29 cells were incubated in the presence of varying doses of soluble HVEM (16). HVEM was found to directly inhibit HT-29 cell growth and its expression up-regulated during the activation of T-cells. These data suggest that HVEM-L interactions could play a direct role in anti-tumor T-cell activation.


LIGHT- Recruitment and Co-stimulation of T cells

LIGHT is a powerful protein that could be used in various ways to elicit positive results in tumor regression. In studies by Zhai et al., Fan et al., and Sandberg et al., LIGHT expression in human tumor cell lines has been shown to stimulate many efficient immune responses. LIGHT triggers the production and secretion of multiple cytokines and chemokines, including IFN-γ. Furthermore, LIGHT triggers the recruitment of various immune cells, such as NK cell and T-cells, which could successfully lead to tumor degeneration (9, 12, 21). Zhai et al. reported that IFN-γ in the presence of LIGHT enhanced apoptotic activity in cancer cells (9). By stimulating IFN-γ, it initiates the flow of communication between cells, triggering the cellular defenses of the immune system. LIGHT and its activation of IFN-γ could stimulate the inhibition of growth, invasion and metastasis of tumor cells, while potentially increasing the level of cytotoxicity in tumor cells, eventually leading to tumor cell eradication. By stimulating NK cells, LIGHT can indirectly activate CTLs. NK cells will induce innate immunity, releasing the necessary perforin granules the tumor cells, thus initiating apoptosis. The stimulation of NK cells is ideal due to its lack of activation by specific antigens needed to kill cells.

LIGHT also shows promise in the presence of CD8+ T-cells. Through combination therapy, LIGHT-mediated treatment in the presence of CD8+ T -cells could directly activate more NK cells. Once the CD8+ T-cells are activated by the tumor cells, they can then release perforin and granzyme granules, activating apoptosis of tumor cells. This activation will discharge more NK cells, which will also induce apoptosis via a perforin pathway. This anti-tumor LIGHT-based therapy could be a great option for cancer patients, by stimulating immune cells, while actively inhibiting tumor cells.

LIGHT was also shown to stimulate the up-regulation of chemokines. Chemokines are effective because they directly control the cells of the immune system. They can guide lymphocytes to the lymph nodes to search for tumor invasion, as well as, recruit dendritic cells to stimulate T-cells. With this treatment, scientists would have to be aware of the immature dendritic cells within the tumor, which could induce tolerance to tumor antigens. The recruitment of mature dendritic cells is ideal because it would produce T-cells and induce a cell-mediated immune response.

LIGHT also shows promise as an effective cancer treatment by manipulating its interactions with its various receptors, HVEM, LTβR, and TR6. Through interaction with HVEM, LIGHT has shown positive host-tumor interaction via co-stimulation of CD8+ T-cells. Since HVEM alone is known for its inhibition of tumor cell growth, while activating T-cells, its interaction with LIGHT is another promising treatment for tumor regression. Consistent proliferation of T-cells specific for tumor cells is the goal of immunotherapy. HVEM-LIGHT pathway may be able to concurrently signal IFN-γ, NK and CD8+ T-cells, establishing a continuous secretion of T-cells throughout the body, eliminating the strength of tumor cells.

Blocking BTLA Inhibition

Since the manipulation of BTLA to block the HVEM-LIGHT pathway has been studied for therapeutic regulation of inflammatory and autoimmune diseases, researchers may want to consider the trio in the immunotherapy of cancer (22). In those tumor cells that do not express co-stimulatory ligands, inducing LIGHT in tumors could increase T-cell proliferation and mediate tumor regression. Maintaining the anti-tumor effects of HVEM-LIGHT, while blocking the inhibitory effects of BTLA, could be a new strategy in tumor immunity. This would promote LIGHT's ability to induce tumor cell death, while stimulating continuous immune cell response and could even be combined with chemotherapy to avoid metastasis at distal tumor sites.


In the case of TR6, it has been shown to restrain CTL and cytokine activity, as well as inhibit LIGHT-mediated tumor cell death. By up-regulating the co-stimulatory properties of HVEM-LIGHT, and blocking the inhibitory properties of TR6, LIGHT-mediated apoptosis could be a successful treatment without the use of its two most prominent receptors, HVEM and LTβR. Although a completely effective cancer immunotherapy treatment has yet to be developed, LIGHT is a promising candidate to be considered. Through manipulation of LIGHT and its receptors, as shown here, LIGHT could be a new wave in stimulating a successful immune response, while also eliciting tumor cell death.

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28. http://www.biolegend.com/media_assets/support_resource/BioLegend_TNF-superfamily.pdf