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Journal of Clinical Oncology, Vol 25, No 10 (April 1), 2007: pp. 1289-1291 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.10.2251
CD57 Expression on Lymphoma Microenvironment As a New Prognostic Marker Related to Immune DysfunctionDivision of Hematology, Azienda Ospedaliera Universitaria Santa Chiara, Pisa, Italy To the Editor: In the December 1, 2006 issue of the Journal of Clinical Oncology, Alvaro et al1 show that a follicular lymphoma (FL) reactive microenvironment infiltrated predominantly by CD57+ T cells is associated with a significantly higher frequency of adverse manifestations, such as "B" symptoms and bone marrow involvement. Recently, Atayar et al2 showed that CD57+ T-cell rosettes occur around neoplastic cells and throughout the nodules in nodular lymphocyte predominance type of Hodgkin's lymphoma. Although these manifestations are surrogate markers for overall survival, a growing amount of evidence points toward CD57 as a marker of general immune dysfunction, independently from the underlying disease. This could be one of the first phenotypic markers shown to have independent prognostic impact in patients with FL. CD57+ cells are predominantly observed outside the neoplastic follicle in FL on the contrary of the diffuse infiltration seen in reactive lymph node hyperplasia.3-5 Expression of CD57, a beta-1,3-glucuronyltransferase defined by the carbohydrate epitope human natural killer (HNK)-1, marks replicative senescence of lymphocytes (clonal exhaustion; ie, the inability to undergo new cell division cycles even after addition of interleukin [IL]-2, IL-7, or IL-15) in response to cognate peptide with costimulation despite the ability to secrete cytokines is preserved.6 Expression of CD57 on CD8+, CD4+, and natural killer cells has been shown to correlate directly with the number of cell divisions, and inversely with telomere length, with a sensitivity greater than presence of CCR7 or lack of CD28. Finally, expression of CD57 renders cells susceptible to activation-induced cell death by apoptosis. So CD57 seems a good candidate to replace the old marker of lymphocyte dysfunction, namely the absence of CD28 and CCR7. In addition to impaired proliferation in response to antigen, migration is also affected: CD8+CD57+ T cells from both HIV and uninfected subjects maintain effective cytotoxic potentials, but are destined to migrate to nonlymphoid tissues without further cycling.7 CD57 antigen is normally expressed only by a minority of human CD8+ T-cell lymphocytes (16%), but more cells express it during chronic immune activation and with increasing age.8,9 The percentage of CD8+CD57+ cells increases in different clinical conditions, especially infections, whose common denominator is immune dysfunction; this includes AIDS,10-12 tuberculosis,13,14 chronic Lyme disease,15,16 measles,17 B19 virus infection18 cytomegalovirus (CMV) disease.13,19 Of interest CMV, not age per se, is the prime driving force behind many or most of the oligoclonal expansions and altered phenotypes and functions of CD8+ T-cell lymphocytes in the elderly.20 CD57+ cells are also increased in other noninfectious diseases, such as common variable immunodeficiency, multiple myeloma, rheumatoid arthritis, autoimmune lymphoproliferative syndrome,21 and after hematopoietic stem-cell transplantation.22 In the latter setting, it has been shown that the conditioning regimen performed before hematopoietic stem-cell transplantation depletes T-cell lymphocytes and causes a novel homeostasis in cell subsets, including increased counts of CD57+ T-cell lymphocytes23,24: a soluble factor released by CD8+CD57+ lymphocytes inhibits cytolytic functions of CD57– effector cognates, creating an immunodeficient status.22,25 It would be intriguing to investigate whether the impact of donor CMV serostatus on overall survival and graft-versus-host disease in haploidentical stem-cell transplantation recipient is somewhat related to increased CD57 counts. It still remains unknown whether the oligoclonal expansion of CD57+ cells25,26 is the predisposing condition or rather the result of antigen selection during a persistent immune activation.27,28 Apart from pathogenetic explanations, CD57 is now become part of a broader picture of immune dysfunction markers. The Swedish octogenarians (OCTO) and nonagenarians (NONA) longitudinal studies distinguished an "immune risk phenotype"29 one important component of which is CMV seropositivity (Table 1).30-32
Why are these clonal expansions of CMV-specific cells and, to a lesser extent, also Epstein-Barr virus (EBV)-specific cells associated with shorter survival? One major finding is that many of the CMV-specific cells in the elderly appear to be anergic and apoptosis resistant. Nonetheless, they also contain sufficient functional CMV-specific cells to maintain immunosurveillance and control CMV disease. Such apoptosis-resistant cells exert suppressive activity on bystander cells. Changes in the EBV-specific response with age are much smaller than those with CMV in the majority of donors (who are, of course, CMV positive),33 whereas in CMV-seronegative donors the response to EBV increases significantly with age.34 Other indications that CMV may hinder immune responses to other pathogens in clinically important situations are the poorer responses to influenza vaccination35 and failure to control HIV in progression to AIDS36 in CMV-seropositive donors. Even if high CD57+ cell counts have a positive prognostic value in some cancer populations undergoing immunomodulatory therapies,37,38 overall their role seems to be negative in human cancers. For human FL, recent microarray studies using whole frozen tissues have provided important insights into the significance of non-neoplastic cells in the lymphoma microenvironment. Of interest, the immune-response 1 signature of non-neoplastic cells, which independently correlated with a survival advantage at multivariate analysis, included several T-cell–restricted genes, but was not merely a measure of the number of tumor-infiltrating T cells because a signature of pan–T-cell genes was not associated with survival. Whether these protective immune response cells represent an active role for immune surveillance in FL remains unanswered, but this work suggests that the random acquisition of oncogenic abnormalities after diagnosis does not have a major effect on survival. Unfortunately no data is currently available to establish the relative contribution of CD57+ cells in these signatures.39 Other studies have shown the impact of other cell subsets on the prognosis of FL. A lymphoma-associated macrophage content fewer than 10 per high-power field is associated with better 15-year overall survival in FL,40 still supporting the importance of microenvironment cells in lymphoma control. Of interest, the impact of lymphoma-associated macrophage on overall survival disappears if patients are treated with anti-CD20 monoclonal antibody rituximab.41 In contrast, high regulatory T-cell numbers predict improved survival of FL patients, while a marked reduction in Tregs is observed on transformation to diffuse large B-cell lymphomas.42 CD57+ cells are likely to be potential culprits in lymphomagenesis and we suggest they could represent a novel parameter to evaluate the effectiveness of immunotherapeutic approaches and risk-tailored therapies. The implications for solid cancers remain to be established. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest.
REFERENCES
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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