The TNFSF Members APRIL and BAFF and Their Receptors TACI, BCMA, and BAFFR in Oncology, With a Special Focus in Breast Cancer.
ABSTRACT: Tumor necrosis factor (TNF) superfamily consists of 19 ligands and 29 receptors and is related to multiple cellular events from proliferation and differentiation to apoptosis and tumor reduction. In this review, we overview the whole system, and we focus on A proliferation-inducing ligand (APRIL, TNFSF13) and B cell-activating factor (BAFF, TNFSF13B) and their receptors transmembrane activator and Ca2+ modulator (CAML) interactor (TACI, TNFRSF13B), B cell maturation antigen (BCMA, TNFRSF17), and BAFF receptor (BAFFR, TNFRSF13C). We explore their role in cancer and novel biological therapies introduced for multiple myeloma and further focus on breast cancer, in which the modulation of this system seems to be of potential interest, as a novel therapeutic target. Finally, we discuss some precautions which should be taken into consideration, while targeting the APRIL-BAFF system.
Project description:It has been shown that B cell activating factor receptor (BAFFR) is critical for B cell development and survival. In this study, we sought to evaluate the expression and function of BAFFR across multiple stains of mice that vary in their potential to develop systemic autoimmune disease. The inability of a commercial antibody to bind to BAFFR in the autoimmune prone mouse strains, MRL and MRL/Lpr led to the discovery of a mutation in TNFRSF13C gene (encoding BAFFR) that resulted in a Pro44Ser substitution in the N-terminus near the BAFF binding site in these strains. To define the biological consequences of mutant BAFFR, we compared the expression and activity of BAFFR in MRL and MRL/Lpr mice to BALB/c, which express the consensus version of TNFRSF13C. B cells from MRL and MRL/Lpr mice expressed mutant BAFFR on surface and were capable of responding to BAFF as exhibited by BAFF-mediated reduction in apoptosis and NF-?B2 activation. Signaling through MAPK ERK1/2 was not significantly induced by BAFF in MRL/Lpr mice; however, MAPK ERK1/2 signaling was intact in MRL mice. The inability of MRL/Lpr B cells to significantly activate ERK1/2 in response to BAFF was due to the high basal activity of the signaling pathway in these cells. In fact, basal activity of ERK1/2 in B cells correlated with the degree of autoimmune susceptibility exhibited by each strain. In addition, aged MRL/Lpr mice with severe autoimmune disease had high BAFF levels, low surface BAFFR, and high basal NF-?B2 activation, a pattern which is attributed to the high frequency of antibody secreting cells. We conclude that P44S BAFFR mutation does not hinder BAFFR function or enhance B cell activity in MRL/Lpr and MRL mice and that other susceptibility loci on the MRL background contributed to the hyperactivity of these cells.
Project description:The TNF family cytokines B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) support plasma cell survival. It is known that inhibitors of BAFF only (BAFFR-Fc) or BAFF and APRIL (TACI-Fc) administered early enough in an NZB/NZW F1 mouse model of systemic lupus erythematosus (SLE) ameliorate clinical outcomes, pointing to a pathogenic role of BAFF. In the present study, TACI-Fc administrated at a later stage of disease, after onset of autoimmunity, decreased the number of bone marrow plasma cells and slowed down further formation of autoantibodies. TACI-Fc prevented renal damage during a 12-week treatment period regardless of autoantibody levels, while BAFFR-Fc did not despite a similar BAFF-blocking activity in vivo. TACI-Fc also decreased established plasma cells in a T-dependent hapten/carrier immunization system better than single inhibitors of BAFF or APRIL, and sometimes better than combined single inhibitors with at least equivalent BAFF and APRIL inhibitory activities. These results indicate that TACI-Fc can prevent symptoms of renal damage in a mouse model of SLE when BAFFR-Fc cannot, and point to a plasticity of plasma cells for survival factors. Targeting plasma cells with TACI-Fc might be beneficial to prevent autoantibody-mediated damages in SLE.
Project description:Recent advances in cancer immunology revealed immune-related properties of cancer cells as novel promising therapeutic targets. The two TNF superfamily members, APRIL (TNFSF13), and BAFF (TNFSF13B), which are type II membrane proteins, released in active forms by proteolytic cleavage and are primarily involved in B-lymphocyte maturation, have also been associated with tumor growth and aggressiveness in several solid tumors, including breast cancer. In the present work we studied the effect of APRIL and BAFF on epithelial to mesenchymal transition, migration, and stemness of breast cancer cells. Our findings show that both molecules increase epithelial to mesenchymal transition and migratory capacity of breast cancer cells, as well as cancer stem cell numbers, by increasing the expression of pluripotency genes such as ALDH1A1, KLF4, and NANOG. These effects are mediated by their common receptor BCMA (TNFRSF17) and the JNK signaling pathway. Interestingly, transcriptional data analysis from breast cancer cells and patients revealed that androgens can increase APRIL transcription and subsequently, in an autocrine/paracrine manner, enhance its pluripotency effect. In conclusion, our data suggest a possible role of APRIL and BAFF in breast cancer disease progression and provide evidence for a new possible mechanism of therapy resistance, that could be particularly relevant in aromatase inhibitors-treated patients, were local androgen is increased.
Project description:Antibodies that target a clinically relevant group of receptors within the tumor necrosis factor receptor superfamily (TNFRSF), including CD40 and CD95 (Fas/Apo-1), also require binding to Fc gamma receptors (Fc?Rs) to elicit a strong agonistic activity. This Fc?R dependency largely relies on the mere cellular anchoring through the antibody's Fc domain and does not involve the engagement of Fc?R signaling. The aim of this study was to elicit agonistic activity from ?CD40 and ?CD95 antibodies in a myeloma cell anchoring-controlled Fc?R-independent manner. For this purpose, various antibody variants (IgG1, IgG1N297A, Fab2) against the TNFRSF members CD40 and CD95 were genetically fused to a single-chain-encoded B-cell activating factor (scBaff) trimer as a C-terminal myeloma-specific anchoring domain substituting for Fc domain-mediated Fc?R binding. The antibody-scBaff fusion proteins were evaluated in binding studies and functional assays using tumor cell lines expressing one or more of the three receptors of Baff: BaffR, transmembrane activator and CAML interactor (TACI) and B-cell maturation antigen (BCMA). Cellular binding studies showed that the binding properties of the different domains within the fusion proteins remained fully intact in the antibody-scBaff fusion proteins. In co-culture assays of CD40- and CD95-responsive cells with BaffR, BCMA or TACI expressing anchoring cells, the antibody fusion proteins displayed strong agonism while only minor receptor stimulation was observed in co-cultures with cells without expression of Baff-interacting receptors. Thus, our CD40 and CD95 antibody fusion proteins display myeloma cell-dependent activity and promise reduced systemic side effects compared to conventional CD40 and CD95 agonists.
Project description:Interactions between APRIL (TNFSF13) and its receptor TACI (TNFRSF13B) are implicated in providing survival benefits for chronic lymphocytic leukaemia (CLL) cells. Here we explored the relationship between TNFSF13 and TNFRSF13B SNPs and expression of APRIL and TACI molecules and performed extended case-control study to evaluate earlier observations. Expression of APRIL and TACI was detected by FACS for 72 and 145 patients, respectively, and soluble APRIL was measured by ELISA in plasma of 122 patients. Genotypes were determined in 439 CLL patients and 477 control subjects with TaqMan Assays or restriction fragment length polymorphism (RFLP). The rs4968210GG genotype of TNFSF13 was associated with a lower percentage of CD19+APRIL+ cells in CLL patients when compared to (AA + GA) genotypes (p-value = 0.027). Homozygosity at rs11078355 TNFRSF13B was associated with higher CD19+ TACI+ cell percentage in CLL patients (p-value = 0.036). The analysis of extended groups of patients and healthy controls confirmed the association of TNFSF13 rs3803800AA genotype with a higher CLL risk (OR = 2.13; CI95% = 1.21; 3.75; p-value = 0.007), while the possession of TNFRSF13B rs4985726G allele (CG + GG) genotype was associated with lower risk of CLL (OR = 0.69; CI95% = 0.51; 0.95; p-value = 0.02). Genetic variants of TNFSF13 and TNFRSF13B may have an impact on APRIL and TACI expression and may be considered as possible CLL risk factors.
Project description:Myeloid cells express the TNF family ligands BAFF/BLyS and APRIL, which exert their effects on B cells at different stages of differentiation via the receptors BAFFR, TACI (Transmembrane Activator and CAML-Interactor) and/or BCMA (B Cell Maturation Antigen). BAFF and APRIL are proteins expressed at the cell membrane, with both extracellular and intracellular domains. Therefore, receptor/ligand engagement may also result in signals in ligand-expressing cells via so-called "reverse signalling". In order to understand how TACI-Fc (atacicept) technically may mediate immune stimulation instead of suppression, we investigated its potential to activate reverse signalling through BAFF and APRIL. BAFFR-Fc and TACI-Fc, but not Fn14-Fc, reproducibly stimulated the ERK and other signalling pathways in bone marrow-derived mouse macrophages. However, these effects were independent of BAFF or APRIL since the same activation profile was observed with BAFF- or APRIL-deficient cells. Instead, cell activation correlated with the presence of high molecular mass forms of BAFFR-Fc and TACI-Fc and was strongly impaired in macrophages deficient for Fc receptor gamma chain. Moreover, a TACI-Fc defective for Fc receptor binding elicited no detectable signal. Although these results do not formally rule out the existence of BAFF or APRIL reverse signalling (via pathways not tested in this study), they provide no evidence in support of reverse signalling and point to the importance of using appropriate specificity controls when working with Fc receptor-expressing myeloid cells.
Project description:The TNF superfamily ligands BAFF and APRIL interact with three receptors, BAFFR, BCMA, and TACI, to play discrete and crucial roles in regulating B cell selection and homeostasis in mammals. The interactions between these ligands and receptors are both specific and redundant: BAFFR binds BAFF, whereas BCMA and TACI bind to either BAFF or APRIL. In a previous phylogenetic inquiry, we identified and characterized a <i>BAFF</i>-like gene in lampreys, which, with hagfish, are the only extant jawless vertebrates, both of which have B-like and T-like lymphocytes. To gain insight into lymphocyte regulation in jawless vertebrates, in this study we identified two <i>BCMA</i>-like genes in lampreys, <i>BCMAL1</i> and <i>BCMAL2</i>, which were found to be preferentially expressed by B-like lymphocytes. In vitro analyses indicated that the lamprey BAFF-like protein can bind to a BCMA-like receptor Ig fusion protein and to both BCMAL1- and BCMAL2-transfected cells. Discriminating regulatory roles for the two BCMA-like molecules are suggested by their differential expression before and after activation of the B-like lymphocytes in lampreys. Our composite results imply that BAFF-based mechanisms for B cell regulation evolved before the divergence of jawed and jawless vertebrates.
Project description:Memory B cells (MBCs) are long-lived cells that form a critical part of immunological memory, providing rapid antibody responses to recurring infections. However, very little is known about signals controlling MBC survival. Previous work has shown that antigen is not required for MBC survival, but a requirement for the B cell antigen receptor (BCR) has not been tested. Other studies have shown that, unlike naive B cells, MBCs do not express BAFFR and their survival is independent of BAFF, the ligand for BAFFR. Here, using inducible genetic ablation, we show that survival of MBCs is critically dependent on the BCR and on signaling through the associated CD79A protein. Unexpectedly, we found that MBCs express BAFFR and that their survival requires BAFF and BAFFR; hence, loss of BAFF or BAFFR impairs recall responses. Finally, we show that MBC survival requires IKK2, a kinase that transduces BAFFR signals. Thus, MBC survival is critically dependent on signaling from BCR and BAFFR.
Project description:The B cell survival factor (TNFSF13B/BAFF) is often elevated in autoimmune diseases and is targeted in the clinic for the treatment of systemic lupus erythematosus. BAFF contains a loop region designated the flap, which is dispensable for receptor binding. Here we show that the flap of BAFF has two functions. In addition to facilitating the formation of a highly active BAFF 60-mer as shown previously, it also converts binding of BAFF to TNFRSF13C (BAFFR) into a signaling event via oligomerization of individual BAFF-BAFFR complexes. Binding and activation of BAFFR can therefore be targeted independently to inhibit or activate the function of BAFF. Moreover, structural analyses suggest that the flap of BAFF 60-mer temporarily prevents binding of an anti-BAFF antibody (belimumab) but not of a decoy receptor (atacicept). The observed differences in profiles of BAFF inhibition may confer distinct biological and clinical efficacies to these therapeutically relevant inhibitors.
Project description:The closely related TNF family ligands B cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL) serve in the generation and maintenance of mature B-lymphocytes. Both BAFF and APRIL assemble as homotrimers that bind and activate several receptors that they partially share. However, heteromers of BAFF and APRIL that occur in patients with autoimmune diseases are incompletely characterized. The N and C termini of adjacent BAFF or APRIL monomers are spatially close and can be linked to create single-chain homo- or hetero-ligands of defined stoichiometry. Similar to APRIL, heteromers consisting of one BAFF and two APRILs (BAA) bind to the receptors B cell maturation antigen (BCMA), transmembrane activator and CAML interactor (TACI) but not to the BAFF receptor (BAFFR). Heteromers consisting of one APRIL and two BAFF (ABB) bind to TACI and BCMA and weakly to BAFFR in accordance with the analysis of the receptor interaction sites in the crystallographic structure of ABB. Receptor binding correlated with activity in reporter cell line assays specific for BAFFR, TACI, or BCMA. Single-chain BAFF (BBB) and to a lesser extent single-chain ABB, but not APRIL or single-chain BAA, rescued BAFFR-dependent B cell maturation in BAFF-deficient mice. In conclusion, BAFF-APRIL heteromers of different stoichiometries have distinct receptor-binding properties and activities. Based on the observation that heteromers are less active than BAFF, we speculate that their physiological role might be to down-regulate BAFF activity.