Response: Decoy receptor 3 (DcR3), a pleiotropic immunomodulator

Roosneck et al speculated that “any protein carrying an HSPG binding domain fused to the Fc portion of IgG may achieve immunosuppression” based on their observation of the inhibitory effects of TACI-Fc versus BCMA-Fc, and Fc-APRIL versus its mutants Fc-APRIL-H98 and ACRP.Fc. They also speculated that this feature is likely to constitute an advantage to use TACI-Fc in autoimmune disorders. The first speculation is in accord with our observation that HBD.Fc, the recombinant protein comprising the heparan sulfate-binding domain (HBD) of DcR3 and Fc portion of human IgG1, functions as DcR3.Fc does to induce dendritic cell (DC) apoptosis.¹  However, more experiments are needed to consolidate this argument, such as using recombinant proteins comprising the consensus sequences of HBD fused with IgG1.Fc to compare their effects with DcR3.Fc and HBD.Fc to induce DC apoptosis,¹  modulate the differentiation and activation of DC and macrophage,^2,3  activate PKC-delta,^1,4  and enhance osteoclast differentiation.⁵  These experiments will provide information to support, or against, their second speculation.

No doubt oligomerized DcR3 is more potent than monomeric DcR3,³  and DcR3 fused with Fc or another tag might enhance DcR3 activity by increasing stability, dimerization, or oligomerization. However, endogenous DcR3 without Fc still has effects similar to DcR3.Fc because the modulatory effects of DcR3.Fc are also observed in transgenic mice overexpressing DcR3.^6,7  Recently, we further demonstrated that DcR3.Fc is able to down-regulate the expression of the master regulator of MHC-II expression (CIITA) in tumor-associated macrophages (TAM) in vitro, and this is confirmed in the TAMs derived from transgenic mice and cancer patients with up-regulated DcR3.⁸  Therefore, like APRIL,⁹  endogenous DcR3 might be able to bind to extracellular matrix or to proteoglycan-positive cells to induce oligomerization, and is as potent as, or similar to, DcR3.Fc.

In addition to interacting with proteoglycan, DcR3 also interacts and neutralizes the functions of 3 members of the tumor necrosis factor (TNF) superfamily: Fas ligand (FasL),¹⁰  LIGHT,¹¹  and TL1A.¹²  Previous studies have shown that DcR3 inhibits FasL-mediated apoptosis⁷  and enhance angiogenesis via neutralizing TL1A in vivo.¹³  Therefore, the newly identified action in DC apoptosis is one of the pleiotropic effects of DcR3 to promote tumor growth.

Several reports have shown that higher serum level of DcR3 correlates with poor prognosis of cancer patients,^8,14-16  and the presence of DcR3 correlates with resistance to 5-fluorouracil–based adjuvant chemotherapy.¹⁷  Therefore, serum level of DcR3 is not only a useful marker to predict cancer prognosis, but is also an important parameter to predict tumor resistance to certain chemotherapy.