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Journal of Clinical Oncology, Vol 25, No 10 (April 1), 2007: pp. 1291-1292 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.10.4851
In ReplyDepartment of Pathology, Hospital Verge de la Cinta, Tortosa, Spain The letter by Drs Daniele Focosi and Mario Petrini outlines their view on CD57 expression as a prognostic marker related to immune dysfunction independently from the underlying disease. It includes some helpful review and comments related to their physiopathologic role, noninfectious and infectious diseases (cytomegalovirus and Epstein-Barr virus), human follicular lymphoma (FL), and the potential role of CD57 in lymphomagenesis and as a parameter of effectiveness of therapy. We would like to report some additional comments related to the fact that in lymphoproliferative syndromes it is probably that not CD57+ cells alone but the global reactive microenvironment that participate in the immune response against the tumor. Firstly, the CD57 expression in the reactive microenvironment of malignant tumors does not seem to have the same impact on clinicobiologic features in FL and Hodgkin's lymphoma (HL). In fact, in our previous reports, a higher frequency of CD57+ cells with an immunity-inhibiting role (immune escape pattern) in FL patients is related to extensive trafficking (low histologic grade) and an aggressive potential1 whereas infiltrated CD57+ cells appear with higher frequency in HL patients with favorable prognostic features (without B symptoms, lower clinical stages, and higher overall survival).2 In our cohort of FL, although the global immune infiltrate (T cells, cytotoxic T lymphocytes [CTL], macrophages, regulatory T cells) is predominantly present in the extrafollicular compartment, T helper-like CD57+ T cells appear in equal proportion in the two compartments (intra- and extrafollicular). In addition, and as a general result of our different immunohistochemical studies in lymphomas, infiltrated cells with cytotoxic potential appear to be of great importance in the prediction of behavior in these patients. CD57 is expressed on a subset of T cells known as natural killer (NK) cells, one of the major effector cells in cellular cytotoxicity with CTLs. T-cell-restricted intracellular antigen (TIA-1) labels cytotoxic granules of generally resting/nonactivated cytotoxic cells whereas perforine and granzyme B (GrB) designated principally activated CTL. Perforin and GrB are constitutively expressed by NK cells whereas they are expressed only on activated CD8+ CTL after antigen recognition. In FL, the quantity of TIA-1+ cells (nonactivated cells) was correlated with the principal infiltrated cells with cytotoxic activity as the exception of CD57+ cells.1 In these patients, these cells have been described as representing another subset of CD4+ T-helper cells that are able to regulate the duration and/or the magnitude of CD4+ T-cell responses by giving instructions for Th2 differentiation or by furnishing T-cell unresponsiveness. In contrast, for HL patients only granzyme B+ cells appear correlated with the CD57+ cells and not TIA-1+ cells, indicating probably that these cells are activated.3 Secondly, immune dysfunction appears effectively a clear denominator in infected patients. Nevertheless, there is evidence that the number of cells with an effective cytotoxic potential differs substantially between patients and not always appreciable changes of the number of CD57+ marker changes in immunocompromised patients. For example, Epstein-Barr virus cases of HL contain high numbers of activated CTLs (GrB) and NK cells, but the cytotoxic immune response appears to be insufficient for, or unrelated to, the elimination of tumoral cells.3 In contrast, in immunosuppressed HIV-infected HL patients, we have observed a significant reduction of intratumoral CD4+ cells, but not a relevant decrease in intratumoral CD8+ T and CD57+ T cells as compared with HIV noninfected HL patients. The pattern of activation of cytotoxic cells showed that 50% of the cytotoxic cells appeared to be activated in HIV noninfected patients, whereas only 8% of the cytotoxic cells expressed GrB in HL.4 Thirdly, an increase of CD57+ cells could be observed in some anomalies of the downregulation of the immune response, such as the autoimmune lymphoproliferative syndrome (ALPS). The alterations of Fas apoptotic pathway are responsible for the chronic lymphoid hyperplasia and autoimmunity characteristics observed in this disorder. Patients with ALPS usually show an expansion of an unusual population of CD4–CD8– T cells (DNTs) that express the alpha/beta T-cell receptor and overexpressed CD57. The expansion of HLA-DR+ T cells and CD57+ T cells appear to be predictive of ALPS disease5, and the expression of CD57, perforin, and other markers suggest a CTL phenotype that has lost CD8 expression. CD57 has been also associated with aging and senescent T cells,6 and high levels of CD57 expression (> 75%) on DNTs supports the theory that these cells are post-terminally differentiated CTLs. Finally, the higher frequency of T lymphocytes but also regulatory T cells and macrophages detected in the reactive microenvironment of our cohort of FL appear significantly associated with a low aggressive potential.1 As Dr Focosi and Dr Petrini indicate, a lower content of lymphoma-associated macrophage is associated with better overall survival in FL,7 but we show that an increase in a specific subset of STAT1-expressing tumor-associated macrophage emerge associated with an adverse outcome.8 In these conditions, STAT1 expression appears then as a marker for increased immune-suppressor activity. In conclusion, although Dr Focosi and Dr Petrini state that CD57 could be considered as a marker of immune dysfunction, in lymphoproliferative syndromes and specially FL, CD57+ cells, but also T lymphocytes, regulatory T cells, cytotoxic cells, macrophages, and plasmacytoid cells are common elements of the reactive microenvironment that appear related with the clinicobiological behavior of the tumor. This suggests that all the cellular elements that make up the immune response against the tumor seem orchestrated in the form of an organized model and that CD57+ cells have different clinicopathological significance in HL and NHL. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest. ACKNOWLEDGMENTS These studies were supported by grants from the Ministerio de Ciencia y Tecnología, Spain (Grants No. G03/179, FIS 02/1637, 04/1467, 04/1440 and 05/0474). REFERENCES
1. Alvaro T, Lejeune M, Salvado MT, et al: Immunohistochemical patterns of reactive microenvironment are associated with clinicobiologic behavior in follicular lymphoma patients. J Clin Oncol 24:5350-5357, 2006 2. Álvaro-Naranjo T, Lejeune M, Salvadó-Usach MT, et al: Tumor-infiltrating cells as a prognostic factor in Hodgkin's lymphoma: A quantitative tissue microarray study in a large retrospective cohort of 267 patients. Leuk Lymphoma 46:1581-1591, 2005[CrossRef][Medline] 3. Alvaro T, Lejeune M, Salvado MT, et al: Outcome in Hodgkin's lymphoma can be predicted from the presence of accompanying cytotoxic and regulatory T cells. Clin Cancer Res 11:1467-1473, 2005 4. Bosch Princep R, Lejeune M, Salvado Usach MT, et al: Decreased number of granzyme B+ activated CD8+ cytotoxic T lymphocytes in the inflammatory background of HIV-associated Hodgkin's lymphoma. Ann Hematol 84:661-666, 2005[CrossRef][Medline] 5. Bleesing JJ, Brown MR, Straus SE, et al: Immunophenotypic profiles in families with autoimmune lymphoproliferative syndrome. Blood 98:2466-2473, 2001 6. Tarazona R, DelaRosa O, Alonso C, et al: Increased expression of NK cell markers on T lymphocytes in aging and chronic activation of the immune system reflect the accumulation of effector/senescent T cells. Mech Ageing Dev 121:77-88, 2000[CrossRef][Medline] 7. Farinha P, Masoudi H, Skinnider BF, et al: Analysis of multiple biomarkers shows that lymphoma-associated macrophage (LAM) content is an independent predictor of survival in follicular lymphoma (FL). Blood 106:2169-2174, 2005 8. Alvaro T, Lejeune M, Camacho FI, et al: The presence of STAT1-positive tumor-associated macrophages and their relation to outcome in patients with follicular lymphoma. Haematologica 91:1605-1612, 2006
Related Correspondence
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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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