Elevated soluble CD 27 levels (TNF-receptor) may predict survival in diffuse large B-cell lymphoma - revisiting “the super- family “ saga.

In this issue of Leukemia and Lymphoma, Goto et al. have evaluated the prognostic significance of sCD27 serum levels in 143 patients with diffuse large B-cell lymphoma (DLBCL) treated with cyclophosphamide, doxorubicin, vincristine and prednisolone plus rituximab (R-CHOP) regimens [1]. Immune staining of biopsied nodes revealed CD27 expression in lymphoma cells in 18% of patients, while in 52%, CD27 was positive in T lymphocytes in the tumor microenvironment but not in lymphoma cells [1]. The highest serum levels of sCD27 were recorded in patients with CD27+ lymphoma cells at biopsy, and were shown to be an independent prognostic factor for overall survival. These observations, which appear significant despite the fact that the patient cohort is small, confirm results published by van Oers et al. in 1993 [2], and later studies reported for indolent lymphomas, primary central nervous system (CNS) lymphoma [3,4] and aggressive non-Hodgkin lymphomas [1,5].

CD27 is a co-stimulatory molecule and a member of the tumor necrosis factor (TNF) receptor super-family [6], and its expression is restricted to the lymphoid lineage. It appears mainly on T lymphocytes but also on B and natural killer (NK) cells. This surface molecule regulates T cell activation [7] and contributes to T cell proliferation and survival, inducing long-term immune memory mainly through expansion of effector memory T cells [7,8]. CD27 functions only upon interaction with CD70, the only known CD27 ligand identified to date, and this well recognized CD70/CD27 pathway appears to regulate the early phase of T cell responses. Activation of the T cell receptor (TCR)/CD3 complex results in up-regulation of CD27 expression, and a soluble form (sCD27) generated by proteolytic cleavage can then be found in the blood and body fluids, particularly in chronic viral infections and autoimmune diseases as well as B-cell malignancies [9].

At this point, one could justifiably pose some questions relating to the CD27/CD70 pathway in T cells as well as its expression on B lymphocytes and B-derived lymphoma cells; for example, what are the underlying mechanisms through which the T-cell CD27 pathway (known to be involved in anti-inflammatory and anti-tumor immune responses) contributes to the growth of lymphoma as reported here by Goto and colleagues [1]? Indeed, it appears that the “TNF super-family” of molecules fulfills a dual purpose in regulating immune function, acting both as an immune stimulator and as an inducer of tolerance, depending on the type of immune response in which it is involved.

What is its role in B cells and B-derived lymphomas? Here it has been shown that CD27/CD70 may aberrantly be expressed on tumor cells, including B-cell malignancies [10,11]. Through their ligation and subsequent activation of signal transduction pathways, they may lead to B-cell proliferation, and play a role in favoring the development of B-cell malignancies.

In this respect, several recent in vitro studies have demonstrated that CD70-expressing B-cell non-Hodgkin lymphomas may favor the generation of regulatory T cells through CD27 co-stimulation, thereby diverting their role toward suppression of immune responses against tumor growth [11]. Moreover, it has been argued that proliferating memory T cells, also generated through CD27 activation, can also differentiate into regulatory T cells, which may well play an important role in tumor immunity [12].

All the above sets the scene for the possible development of a new humanized anti-CD70 antibody that could possibly block this pathway [11]. Blocking the CD70 pathway may have several advantages in the treatment of solid tumors, since, as in normal tissues, CD70 expression is restricted to cells of hematopoietic origin, while its aberrant expression is limited to cancer cells [13]. This would help to achieve optimal targeting specificity and limit potential side effects. In fact, in vitro studies already imply that anti-CD70 antibodies may be useful for the treatment of CD70 + B-cell lymphomas [14], and hence this may still prove to be a potential novel approach in the future.

We may thus conclude that Goto et al. [1] show that patients with DLBCL with higher circulating levels of sCD27 appear to have a poorer prognosis than those with lower levels. This was more frequently encountered in patients whose biopsied B-cell lymphoma cells were positive for CD27 than in those with CD27-negative B-cell tumors but with CD27-positive non-malignant T cells present in the microenvironment. Despite the fact that the laboratory standardization of measurement and cut-off levels for soluble cytokines remain problematic in this field, the findings relating to prognostic significance of sCD27 serum levels appear to have an independent value on multivariate analysis and correlate with some of the recognized conventional clinical parameters included in the International Prognostic Index (IPI) score.

This significant observation remains of great interest, as the techniques used to determine the levels of sCD27 are economical to employ and simple to perform. They could feasibly serve as an adjunct to the IPI score and be used as a guide to tailor optimal therapy for some patients with DLBCL, particularly those with high risk disease (as determined by routine IPI scoring), who are expected to have a poor response to optimal chemoimmunotherapy currently employed.

Potential conflict of interest

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