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© 2003 American Society for Clinical Oncology
Emerging Applications of the Tumor Necrosis Factor Family of Ligands and Receptors in Cancer Therapy
From the Department of Lymphoma and Myeloma, University of Texas M.D. Anderson Cancer Center, Houston, TX; and the Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA. Address reprint requests to Anas Younes, MD, Department of Lymphoma and Myeloma, Unit 429, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: ayounes{at}mail.mdanderson.org.
Abnormalities of the tumor necrosis factor (TNF) family members have been linked to several human diseases, including cancer. Novel treatment strategies for cancer are emerging based on an understanding of the function of TNF family members. The advantage of these strategies is their potential to selectively target cancer cells, while sparing normal cells. Combining these new strategies with currently available treatments such as chemotherapy and radiation therapy is under investigation, with promising results. However, because some TNF family members are toxic to normal mammalian cells when administered systemically, only a few TNF family members have potential therapeutic value. This concise review focuses on the clinical implications of four TNF family members for cancer treatment: CD30/CD30 ligand, CD40/CD40 ligand, receptor activator of nuclear factor-  B (RANK)/RANK ligand, and TNF-related apoptosis-inducing ligand (TRAIL) Apo-2L/TRAIL receptors.
MEMBERS OF the tumor necrosis factor (TNF) family of ligands have pleiotropic biologic functions. Many of these ligand/receptor pairs are involved in the growth regulation of normal cells by inducing apoptosis or enhancing cell survival and proliferation. The balance of these opposing functions is critical for maintaining normal cellular homeostasis. In addition to regulating cell death and survival, some TNF family members are involved in regulating the immune response and bone metabolism. Additional studies are being conducted to evaluate the potential clinical use of some of these ligand/receptor pairs in tumor vaccine therapy and treatment of hypercalcemia associated with cancer. This field is rapidly developing, and several of these molecules are entering clinical trials. Understanding the basic function of these molecules and the rationale for clinical testing will help to design novel treatment strategies for cancer patients.
To date, members of the TNF family include 26 receptors and 18 ligands. Although the majority of the TNF family members consist of ligand/receptor pairs, some ligands have more than one receptor, and some receptors are shared between more than one ligand. The biologically active forms of these protein ligands and receptors are self-assembled protein trimers. These trimers do not share any sequence homology at the receptor-binding site, but they do share 25% to 30% sequence homology at trimerization sites. The ligands are either type II transmembrane proteins (N-terminal inside the cell and C-terminal outside the cell) or soluble proteins.1 Similarly, the receptors can exist in either transmembrane (type I proteins) or soluble forms. These receptors are characterized by the presence of 40-amino-acid, cysteine-rich repeats in the extracellular domains.2,3 The intracellular domains of these receptors share no sequence homology, accounting for their diverse biologic functions. The cytoplasmic tails signal by interacting with two major groups of intracellular proteins: TNF receptor–associated factors (TRAFs) and death domain– (DD-) containing proteins.4 There are at least six human TRAFs that can interact with TRAF-binding sites on the cytoplasmic tail of some of these receptors to initiate several signaling pathways, including mitogen-activated protein kinases (MAPK), Akt, and nuclear factor-
CD30 is a 120-kDa type I transmembrane protein that contains six cysteine-rich repeat motifs in its extracellular domain (Fig 1  ).5 Like many TNF receptors, CD30 can be shed in a soluble form (sCD30). An 85-kda sCD30 can be detected in culture supernatants of CD30+ cell lines and in sera of patients with CD30+ tumors. In healthy individuals, CD30 expression is restricted to activated B and T lymphocytes. CD30 expression has been observed in several nonmalignant disorders, including lymphomatoid papulosis, and in virally transformed B and T cells.6–11 CD30 is also expressed in several types of malignancies, including Hodgkin’s disease, anaplastic large-cell lymphoma, immunoblastic lymphoma, multiple myeloma, adult T-cell lymphoma leukemia, mycosis fungoides, germ-cell malignancies, and thyroid carcinoma.12–19 Soluble CD30 is detected at low levels in the sera of healthy individuals and in individuals infected with one of several different viruses, including hepatitis B and C, human immunodeficiency virus (HIV), and Epstein-Barr virus (EBV), and at higher levels, in individuals with systemic lupus erythematosis, rheumatoid arthritis, and Hashimoto’s thyroiditis.20–26 Elevated levels of soluble CD30 in sera from patients who have anaplastic large-cell lymphoma or Hodgkin’s disease have been reported to correlate with a poor prognosis.21,27,28
CD30L (CD153) is a type II transmembrane protein that belongs to the TNF family.29,30 The human CD30L gene has been mapped to chromosome 9q33. CD30L is expressed in a wide variety of hematopoietic cells16,30–36 in addition to epithelial cells and Hassall’s corpuscles in the thymus medulla.37 Consequently, several hematopoietic tumors also express CD30L, including chronic lymphocytic leukemia (CLL), follicular B-cell lymphoma, hairy cell leukemia, T-cell lymphoblastic lymphoma, and adult T-cell leukemia lymphoma.16,31,32
CD40 is a 50-kda type I transmembrane protein.11,38–41 The extracellular segment of CD40 contains four cysteine-rich repeats that are characteristic of other members of the TNF receptor family (Fig 1
The receptor activator of nuclear factor-
TRAIL (Apo2 ligand) is a death protein that shares the highest sequence homology with Fas ligand (28%) and TNF alpha (23%).76–78 TRAIL has four exclusive receptors79–81: TRAIL-R1 (DR4),82 TRAIL-R2 (DR5, KILLER, TRICK2),83–89 TRAIL-R3 (DcR1, TRID, LIT), and TRAIL-R4 (DcR2, TRAIL-R4, TRUNDD). TRAIL-R1 and -R2 are death receptors that contain a DD in their intracellular tail, whereas TRAIL-R3 and -R4 do not transduce apoptotic signals (Fig 1
CD30, CD40, and RANK share several common signaling features, yet they have diverse biologic functions (Table 1 ). They signal through TRAFs, activate NF-kB, and induce cytokine and chemokine secretion. The cytoplasmic tail of CD30 contains several TRAF-binding sequences that can bind TRAF-1, -2, -3, and -5,96–98 and activate NF-B.96,98 Overexpression of CD30 by Reed-Sternberg cells can lead to self-aggregation, recruitment of TRAF-2 and TRAF-5, and NF-B activation, independent of CD30L.99 The exact biologic function of CD30 and CD30L in healthy individuals remains poorly understood, as no human diseases have been linked with defects of the CD30 and CD30L genes.100–102 However, recent studies suggested that CD30L may have a role in T- and B-cell costimulation, cytokine and chemokine secretion,103–108 and possibly T-cell–negative selection and removal of autoreactive thymocytes. CD30L has been shown to have diverse activity in CD30+ tumor cell lines, ranging from enhancement of survival to growth inhibition and induction of apoptosis.30,109–112 Several types of malignant hematopoietic cells can express biologically active membrane-bound CD30L.16,32 In some cases of primary cutaneous CD30+ T-cell lymphoma, coexpression of CD30 and CD30L has been proposed to be responsible for the spontaneous regression often observed in this disease.113 CD40 activates TRAF-2, -3, -5, and -6,114 leading to the activation of diverse signaling pathways, including extracellular signal-regulated kinase (ERK), c-jun amino terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and NF-B.11,41 CD40L is important for priming dendritic cells to activate CD8+ cytotoxic T cells,115 and it plays a critical role in B-cell survival, proliferation, differentiation, and immunoglobulin isotype switching.41 Furthermore, CD40L enhances antigen presentation by upregulating CD80 (B7.1) and CD86 (B7.2) costimulatory molecules. The CD40L gene is located on chromosome X. An inherited deficiency of CD40L causes the X-linked hyper IgM syndrome, which is characterized by severe immune impairment.116–118 In contrast, sustained constitutive expression of CD40L in transgenic mice has been reported to cause both benign and malignant T-cell lymphoproliferative diseases.119 The role of the CD40L/CD40 pathway in CD40-expressing tumors has been extensively studied with conflicting results, perhaps because of the pleiotropic functions of CD40L in different cells. RANK activates TRAF-1, -2, -3, -5, and -6,120–122 leading to the activation of several signaling pathways, including NF-B, AKT, JNK, ERK, p38, and STAT3.61,73,123–125 The physiologic significance of the RANKL/RANK pathway has been demonstrated in knockout experiments in which RANK-/- or RANKL-/-mice showed profound defects in bone resorption (osteopetrosis), lymph node formation, and B-cell development.62,126–128 In contrast, OPG-/- mice developed osteoporosis and hypercalcemia.66,129 In humans, homozygous deletion of the OPG gene has been associated with Paget’s disease.130 Thus, the balance between RANKL and its two receptors is critical for bone and calcium homeostasis. Not surprisingly, this balance is shifted towards bone resorption in several human diseases, including post menopausal osteoporosis, Paget’s disease, cancer-associated bone lytic lesions, and hypercalcemia, including adult T-cell lymphoma/leukemia.131,132 As shown in Figure 2, hematopoietic stem cells generate osteoblast stromal cells that can be stimulated by cytokines and hormones to express RANKL. RANKL binds to RANK on osteoclast precursor cells, leading to their activation. Activated osteoclasts can cause bone resorption and lytic bone lesions. Both androgens and estrogens can suppress RANKL expression, which could explain the increased incidence of osteoporosis in hormone-deficient elderly men and women.133,134 In cancer patients, cancer cells usually indirectly activate osteoclasts by upregulating RANKL on osteoblast stromal cells. Occasionally, cancer cells may express RANKL and secrete soluble RANK and directly activate the osteoclasts.74,75,132,135 OPG inhibits the effects of RANKL on osteoclasts both in vitro and in vivo. It is, therefore, not surprising that serum OPG levels are decreased in patients with multiple myeloma and Paget’s disease.130,136,137 In contrast, patients with advanced prostate carcinoma, Hodgkin’s disease, and non-Hodgkin’s lymphoma have elevated levels of serum OPG.136,138 The malignant cells of Hodgkin’s disease and non-Hodgkin’s lymphoma have been reported to express OPG, which might be the source of elevated serum OPG in these patients.73 Considerable interest has been generated regarding the potential role of the RANKL/RANK axis in multiple myeloma. Emerging data suggest that myeloma cells secrete factors and cytokines that upregulate RANKL expression and downregulate OPG expression in stromal cells and bone microenvironments, thereby shifting the balance toward bone resorption.137,139–141 However, myeloma cells may also express RANKL and directly activate osteoclasts.75,135 In addition to the critical role of RANKL/RANK in bone metabolism, RANKL also enhances survival and function of dendritic cells65,142 and plays a role in mammary gland development143 and angiogenesis.144
The primary function of TRAIL is to induce cell death by activating its death receptors TRAIL-R1 and TRAIL-R2. TRAIL induces cell death by direct activation of caspases (extrinsic receptor-mediated pathway), but it can also activate the mitochondria-intrinsic pathway by cleaving Bid (Fig 3 ). In some cell types, both pathways are activated, while in others, only one pathway is preferentially activated. In the extrinsic receptor-mediated pathway, TRAIL-R1 and -R2 recruit a Fas-associated DD adapter protein, which in turn recruits caspase-8 and caspase-10, leading to activation of the execution caspase-3, -6, and -7, and subsequent cell death (Fig 3).2,4,145–149 TRAIL can also activate the intrinsic pathway of mitochondria. Activated caspase-8 can cleave Bid, which promotes Bax and Bak activation and oligomerization, leading to mitochondrial membrane damage and cytochrome C release and subsequent activation of caspase-9. Active caspase-9 can then activate the execution caspase-3, -6, and -7 (Fig 3). In addition to activating death pathways, TRAIL can also activate NF-B and JNK.91,150–152 Although overexpression experiments have suggested that TRAIL-R3 and TRAIL-R4 can protect cells from TRAIL-mediated apoptosis, several recent studies report that expression of TRAIL-R3 and TRAIL-R4 in cancer cell lines does not predict protection from TRAIL.153–155 TRAIL has an important physiologic role in tumor immune surveillance. Both TRAIL-deficient (TRAIL-/-) mice and mice that receive treatment using an anti-TRAIL blocking antibody are more susceptible to tumor initiation and metastasis.156,157 The protective antitumor function of TRAIL is predominantly mediated by TRAIL-expressing NK cells.157 Other recent data suggested that TRAIL may also play a role in regulating cytokine and chemokine expression.158,159 Several mechanisms of resistance to TRAIL have been reported in different cell lines, including TRAIL receptor mutations, cFLIP overexpression, caspase-8 deficiency, Bax deficiency, Bcl-2 overexpression, inhibitor of apoptosis family of proteins overexpression, NF-B activation, protein kinase C activation, and constitutive ERK 1/2 and AKT expression.95,160–175 Several types of tumor cells may not express caspase-8 because of genetic hypermethylation. Pharmaceutical demethylation of the caspase-8 gene results in re-expression of caspase-8 and may restore sensitivity to TRAIL.176 In another study, inhibition of NF-B expression by the proteosome inhibitor N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal or transient inhibitor B (IB) expression, markedly increased the sensitivity of lymphoid tumor cells to TRAIL.177 Similar to FasL, TRAIL can be expressed in tumor cells, including myeloid, lymphoid, breast, and brain tumor cells.153,178–180 In one study, tumor cells killed target Jurkat cells via a TRAIL-specific mechanism.180 However, the significance of TRAIL expression in tumor cells in vivo remains unknown.
CD30/CD30L Because CD30 expression is restricted to a small number of normal cells, its expression in malignant cells makes it a good target for antibody therapy (Table 2 ). However, because CD30 triggering may produce paradoxical effects in different CD30+ cells, choosing a therapeutic anti-CD30 antibody should be performed carefully. Recently, a chimeric anti-CD30 antibody was reported to induce cell-cycle arrest and apoptosis in Hodgkin’s-derived cell lines, and is currently being evaluated in a phase I study in patients with relapsed Hodgkin’s disease and other CD30+ hematologic malignancies.181 Unconjugated anti-CD30 antibodies have been effective in prolonging survival of mice bearing chemotherapy resistant human CD30+ anaplastic large cell lymphomas.182,183 In addition to the use of unconjugated anti-CD30 antibodies, both bispecific antibodies184 and immunotoxin conjugates185–190 have been evaluated, with promising results.
CD40/CD40L The optimal use of the CD40L/CD40 pathway in cancer therapy remains controversial because of conflicting reports of CD40L activity against cultured and primary cancer cells in vivo and in vitro. CD40 is expressed in B-cell lymphoid malignancies and in several types of solid tumors. Depending on the tumor type, CD40 activation can lead to cell proliferation, and survival or growth arrest and apoptosis in vitro.160 In vivo activation of CD40 is complicated by the added immunologic functions of the CD40/CD40L system. In general, CD40L is a survival factor for normal B cells. This prosurvival function seems to be maintained in the majority of primary B-cell malignancies in vitro.191–198 However, when B-cell lines were studied, CD40 activation was reported to either promote survival or to induce cell growth arrest and apoptosis. Furthermore, when freshly isolated primary malignant B-cell tumors were stimulated with CD40L or activating anti-CD40 antibodies, they became resistant to chemotherapy and Fas ligand, presumably because of upregulation of antiapoptotic molecules, including Bcl-xL, Mcl-1, NF- B, survivin, and cFLIP.199–202 Finally, because CD40L and CD40 can be coexpressed by several types of B-cell malignancies, an autocrine/paacrine CD40L/CD40 survival loop has been proposed to play a role in the pathogenesis and survival of some B-cell neoplasms.203 A similar survival loop was recently proposed for cutaneous T-cell lymphoma204 and large B-cell lymphoma.60 The complexity and diversity of CD40/CD40L functions led some investigators to consider opposing therapeutic strategies, as the optimal use of the CD40/CD40L system in lymphoid malignancies has not been determined. One strategy is to therapeutically interrupt CD40/CD40L interaction, to deprive malignant lymphocytes from this survival and chemotherapy resistance loop. This can be achieved by anti-CD40L or anti-CD40 blocking antibodies. A completely different strategy is to take advantage of the role of CD40 activation in generating therapeutically effective T-cell–mediated antitumor responses205–209 by upregulating the expression of the costimulatory molecules CD80 (B7.1) and CD86 (B7.2) in malignant B lymphocytes.197,210 This observation has generated some enthusiasm for the use of CD40L in cancer immunotherapy and vaccines.211–214
The potential therapeutic use of the CD40/CD40L system in human cancer has been recently evaluated in two phase-I studies. The first study evaluated recombinant human CD40L (rhuCD40L) in patients with relapsed solid tumors and aggressive lymphoma.215 Nine patients with non-Hodgkin’s lymphoma (8 with B-cell and 1 with T-cell histology) were included. Patients received rhuCD40L by five daily subcutaneous injections every 4 to 6 weeks. One patient with T-cell lymphoma achieved a partial response, while none of the 8 patients with B-cell lymphoma responded.215,216 A second phase I study was based on extensive preclinical data and used a CD40L gene transfer approach in patients with relapsed CLL.217 After a single bolus infusion of autologous CLL cells that were transfected ex vivo with the CD40L gene, patients had increased plasma levels of IL-12 and interferon-
RANKL and Its Receptors TRAIL and its receptors. The preferential activity of TRAIL against cancer cells has generated hopes for its potential use in cancer therapy alone or in combination with chemotherapy and radiation therapy. In fact, TRAIL has some antitumor activity against the majority of human cancer cell lines, including those derived from colon, lung, breast, kidney, prostate, brain, pancreas, skin, and hematopoietic cells.219–229 Most importantly, TRAIL-induced apoptosis is independent of p53 status, which makes it potentially effective against tumors that are resistant to chemotherapy.230,231 In several tumor types, including colon, breast, glioma, and urinary bladder carcinoma, the activity of TRAIL was enhanced by chemotherapy (etoposide, cisplatin, lomustine, fluorouracil, doxorubicin, camptothecin) or radiation therapy in vitro and in vivo, presumably by upregulating TRAIL-R1 and -R2, or by downregulating cFLIP expression.219,232–238 Promising in vivo results against human colon, breast, and brain tumors were reported in xenografted SCID or nude mice.219,239,240 In these experiments, TRAIL activity was also enhanced by chemotherapy. Unlike FasL and TNF, which are clearly toxic to liver cells and cannot be used therapeutically, the in vivo toxicity of TRAIL to hepatocytes remains controversial, but it may be reduced by carefully selecting nontoxic protein preparations.241,242 Recently, the use of an anti–TRAIL-R1 or anti–TRAIL-R2 monoclonal antibody was found to be as effective as TRAIL in killing tumor cells, and it was not toxic to normal human hepatocytes.243,244 These antibodies also enhanced the effects of chemotherapy. Because several investigators are using different preparations of TRAIL, it remains to be determined whether certain versions of recombinant TRAIL and anti-TRAIL receptor antibody therapy can maintain this preferential antitumor effect while sparing normal tissue. The potential clinical utility of TRAIL in cancer therapy will be determined in well-designed clinical trials using a safe TRAIL formulation, or anti-TRAIL receptor antibodies.
In addition to using monoclonal antibodies, the use of small molecules that inhibit specific and critical survival signals in cancer cells is under intensive investigation. The success of imatinib in the treatment of patients with chronic myelogenous leukemia has provided solid support for the use of small molecules in cancer therapy. Some transmembrane receptors contain kinase activity in their cytoplasmic tails that can be targeted by small interfering molecules. The best examples of this class of receptors are the epidermal growth factor and c-Kit receptors. Although the TNF family receptors have no kinase activity, small molecules can be used to target downstream survival signals that are activated by these receptors. These downstream signals, however, are not specific for the TNF receptors, as they are frequently shared with other receptors. Examples include specific inhibition of the NF- B and mitogen activated protein (MAP) kinase pathways. Interfering with these pathways has been shown to inhibit proliferation, and/or to induce cell death of several tumor types in preclinical testing.245–248 Furthermore, inhibition of these signaling pathways has been shown to potentiate the effect of chemotherapy and TRAIL.171,246,248,249 Levi et al250 demonstrated antiproliferative effects on CD30+ cutaneous anaplastic large cell lymphoma by specific inhibitors of ERK/MAP kinase (UO126), and an inhibitor that competes specifically for nuclear binding of NF-kB (SN50). Izban et al251 demonstrated apoptosis of cutaneous T-cell lymphoma cell lines by chemical inhibitors of NF-kB, specifically gliotoxin, MF132, BAY 11–7082, and BAY 11–7085. NF-kB activity of Hodgkin’s and Reed-Sternberg cells can also be blocked by proteosome inhibitors.252 Thus, small molecules can augment the therapeutic armamentarium, which can target TNF receptor family members and their downstream signaling pathway in cancer cells. Future treatment programs will likely test a combination of small molecules, antibodies, and traditional chemotherapy agents.
The authors indicated no potential conflicts of interest.
We thank Noelle Heinze for editorial assistance.
Supported by NIH grants P30 CA 26672 (AY) and P0 CA 93683 (MEK).
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ABSTRACT
INTRODUCTION
) sequences, which are capable of activating death pathways. TNF-related apoptosis-inducing ligand (TRAIL; Apo2 ligand) can bind to 4 exclusive receptors (TRAIL-R1, TRAIL-R2, TRAIL-R3, and TRAIL-R4), and to osteoprotegerin (OPG), which is a soluble receptor that is shared with the Rank ligand. Both TRAIL-R1 and TRAIL-R2 intracellular tails contain a DD and can induce cell death. TRAIL-R3 and -R4 do not induce cell death, as -R3 lacks a cytoplasmic tail and -R4 has an incomplete DD (
).
, an increase in total peripheral blood and CLL-specific T-cell counts, and regression of their lymphadenopathy.