Figure 1. CD27/CD70 signaling pathway
CD27 and CD70 molecules are typical members of the tumor necrosis factor (TNF). So CD27 is also known as the tumor necrosis factor receptor superfamily 7(TNFRSF7), and its ligand is called tumor necrosis factor ligand superfamily 7(TNFLSF7). Similar to other TNFSF ligands, CD70 is expressed as a single spanning transmembrane protein with an extracelluar domain comprising a stalk region. Several ligands of the TNFSF molecules have been described that are naturally generated by proteolysis in the stalk region or by alternative splicing. The possible natural occurrence of CD70 forms has been poorly addressed so far but various recombinant variants of CD70 containing the THD have been investigated and found to be able to interact with CD27.
In its N-terminal extracellular domain, CD27 contains two complete and one incomplete version of the cysteine rich domain (CRD), which is characteristic for the TNFRSF. These TNFRSFs can be divided into three categories: First, death receptors, which frequently induce apoptosis and whose intracellular domains contain a protein-protein interaction domain called death domain. Second, TNF receptor-associated factors (TRAF)-interacting receptors that interact by help of short peptide motifs with trimeric adapter proteins of the TRAF family and third, decoy receptors lack its own authentic signaling capabilities that act by regulating signal transduction of receptors of the two other groups of TNFRSF receptors. CD27 belongs to the TRAF interacting subgroup of the TNFRSF and interacts with TRAF2, TRAF3 and TRAF5 by help of a single TRAF-interacting peptide motif. Membrane CD70 strongly stimulates CD27-associated signaling pathways while CD70 molecules are not necessarily able to trigger CD27-associated signaling pathways. It has been found that a recombinant form of CD70 comprising the complete extracellular domain of the molecule acts as an efficient stimulator of CD8+ T-cells. In contrast, a somewhat shorter recombinant form of CD70 consisting of the THD but lacking the major part of the stalk region of the molecule still binds CD27 but was found to be unable to trigger efficient CD27 signaling despite receptor binding. It is worth mentioning that CD27 and other TNFRSF receptors that are not or poorly activated by ligand molecules are readily and efficiently stimulated upon dimerization or oligomerization of the ligand trimers. Taken together, in view of the available evidence, it is tempting to speculate that membrane CD70, but not CD70 trimers, induces supramolecular CD27 clusters composed of signaling competent (CD272) 3-(CD703) 2 complexes.
The function of pathway
From previous introduction, we can know that CD27 belongs to a subgroup of T-cell co-stimulatory TRAFs that interact with TNFSF receptors and activate signaling pathways resulting in activation of transcription factors of the NFκB family and MAP kinases. By activating these pathways, CD27 can enhance cellular proliferation and expression of anti-apoptotic proteins. In this process, activation of CD27 results in recruitment of TNF receptor associated factor-2 (TRAF2) and perhaps TRAF5 and/or NFκB inducing kinase (NIK) to CD27. This interferes with the constitutive degradation of NIK in the cytoplasm which is triggered by the E3 ligases cellular inhibitor of apoptosis-1 (cIAP1) and cIAP2 in cooperation with TRAF2 and TRAF3. As a consequence, there is the activation of the alternative NFκB pathway. CD27-associated TRAF2 and NIK furthermore stimulate the activation of the classical NFκB pathway. In analogy with other better-studied TNFSF receptors, this might involve transactivation of cIAPs and the inhibitor of κB kinase complex consisting of NEMO and IKK2. Besides, CD27 activation also leads chronic myelogenous leukemia (CML) cells to TRAF2-triggered TRAF2 and NCK interacting kinase (TNIK)-mediated activation of T-cell factor 4 (TCF4)/β-catenin-driven transcription. There is early but yet unconfirmed evidence that the interaction of CD27 with SIVA could furthermore result in apoptosis induction by poorly understood mechanisms.
The expression of CD70 is highly regulated and only occurs in healthy individuals transiently on activated T-cells, antigen and Toll-like receptor-stimulated B-cells, mature dendritic cells, NKcells and on dendritic and epithelial cells of the thymic medulla. CD27 is expressed on the surface of naive and memory T-cells and its expression on these cells further increases after T-cell activation. In contrast, CD27 expression is typically downregulated in long-term cultured and differentiated CD8+ T-cells. In addition, γδ T-cells, memory B-cells, NK-cells but not naive B-cells express CD27, too, and there is again enhanced expression in T-cell dependent B-cell responses. However, there is no evidence of CD27 expression in human common progenitors of monocytes, osteoclasts and dendritic cells. In accordance with its prominent T-cell associated expression pattern, the CD70-CD27 system has been implicated in various aspects of T-cell biology including:①Costimulation and expansion of naive CD4+ and CD8+ T-cells.②Differentiation to memory CD8+ T-cells.③Survival of cytotoxic T-cells in nonlymphoid tissue by autocrine IL2 induction triggered by B-cell and DC expressed CD70.④Enhancement of Th1 differentiation.⑤Inhibition of Th17 effector cell differentiation.⑥Costimulation and expansion of Th1-biased interferon-γ producing γδ T-cells. Besides, in T-cell dependent B-cell responses, CD27 enhances the expansion of activated B-cells and their differentiation to plasma cells and contributes to the development of germinal centers.
The study found that enforced CD27 signals similarly prevent tumor growth. For instance, approximately a third of patients with germ line deficiencies in CD27 or CD70 present with Hodgkin lymphoma or diffuse large B-cell lymphoma, and somatic mutations or deletions in CD70 are frequently observed in diffuse large B-cell and Burkitt lymphomas, confirming that CD27/CD70 signals also contribute to antitumor immunity in humans. As is becoming increasingly apparent in mAb therapies, the efficacy of varlilumab (anti- CD27 mAb) is dependent on its interaction with FcRs in the host. Intriguingly, varlilumab acts as a direct T-cell agonist and also depletes human lymphoma cells in immune-deficient mice; whether the mechanism of action is linked to the relative expression levels of CD27 on the target cell population and/or the local FcR milieu remains to be clarified. Clinically, early indications are that varlilumab is well tolerated and exhibits biological activity consistent with activation of the CD27 pathway, including chemokine induction, particularly IP-10 (CXCL10), and expansion of activated and effector T cells. Importantly, this first-in-human trial shows that varlilumab is clinically active, achieving responses similar to those observed with anti-OX40.
Besides, CD70 is aberrantly expressed by some tumor types including renal-cell carcinoma, in which CD70 drives terminal differentiation of responding T cells, and in chronic lymphocytic leukemia, CD70 confers proliferative signals to the tumor. In addition, human chronic myeloid leukemia stem cells receive proliferative signals via the Wnt pathway following CD27 engagement, and acute myeloid leukemia stem cells were recently shown to express both CD27 and CD70, an interaction that promotes their survival. Encouragingly, a blocking anti-CD70 mAb prevented the growth of acute myeloid leukemia blast cells in a xenotransplantation model. These studies suggest that mAbs that either block CD70 signals or deplete CD70+ tumor cells would be an appropriate therapeutic strategy for some tumors. To date, an anti-CD70 mAb is well tolerated in renal carcinoma and NHL patients with some evidence for improved stabilization of disease at higher doses.