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© 2001 American Society for Clinical Oncology
CD8+ T Cells in Cutaneous T-Cell Lymphoma: Expression of Cytotoxic Proteins, Fas Ligand, and Killing Inhibitory Receptors and Their Relationship With Clinical BehaviorByFrom the Departments of Dermatology and Pathology, Free University Hospital, Amsterdam, the Netherlands. Address reprint requests to M.H. Vermeer, MD, Department of Dermatology, Leiden University Medical Center, Albinusdreef 2 2300 RC Leiden, the Netherlands; email: m.h.vermeer{at}lumc.nl
PURPOSE: We investigated the number, phenotype, and prognostic significance of CD8+ T cells in patients with mycosis fungoides (MF) and CD30- primary cutaneous large T-cell lymphoma (PCLTCL). PATIENTS AND METHODS: Immunohistochemical stainings for CD8, granzyme B (GrB), T cell–restricted intracellular antigen (TIA-1), Fas ligand (FasL), and killer-cell inhibitory receptors (KIRs; CD95, CD158a, and CD158b) were performed on 83 first-diagnostic biopsy samples obtained from patients with plaque-stage MF (n = 42), tumor-stage MF (n = 20), and CD30- PCLTCL (n = 21). RESULTS: Serial sections and double-staining experiments showed that the large majority of CD8+ T cells in MF and CD30- PCLTCL expressed TIA-1 and FasL, whereas only a minority expressed GrB, which suggested that these CD8+ T cells were partly activated cytotoxic T lymphocytes (CTLs). These CD8+ CTLs never or rarely expressed KIRs. This phenotype was a constant feature of CD8+ CTLs and did not alter with disease progression. In contrast, the median percentage of CD8+ CTLs in plaque-stage MF (22%), tumor-stage MF (7%), and CD30- PCLTCL (3%) differed significantly (P < .0001) and was associated with a significant decrease in 5-year survival. Also within the group of tumor-stage MF, a significant relation between CD8+ CTLs and survival was found. Multivariate analysis in the total group of MF demonstrated that both skin stage and percentage of CD8+ CTLs were independent parameters of survival. CONCLUSION: Our results demonstrated that partly activated CD8+ CTLs were present in CTCL and that high proportions of these cells correlated with a better prognosis. This suggested that these CD8+ CTLs could play an important role in the antitumor response in these conditions.
CUTANEOUS T-CELL lymphomas (CTCLs) are a group of non-Hodgkin’s lymphomas mainly with a CD3+CD4+ memory T-cell phenotype that preferentially home to the skin.1 Mycosis fungoides (MF), the most common type of CTCL, is characterized by erythematous, scaly patches, and plaques in the early stages of disease and generally has an indolent clinical course.2 However, in some patients, progression to tumor-stage MF is observed, which is associated with more aggressive clinical behavior. In contrast, patients with CD30- primary cutaneous large T-cell lymphoma (PCLTCL) generally present with multiple tumors that rapidly spread to extracutaneous sites, and these patients have a poor prognosis, with a 5-year survival rate of 15%.1 The pathophysiologic mechanisms underlying these differences in biologic behavior are largely unknown. However, the protracted clinical course in most MF patients, the beneficial effect of immunomodulating therapies, and the influx of CD8+ cytotoxic T lymphocytes (CTLs) in regressing MF tumors on intralesional administration of interleukin-12 suggest that a tumor-specific immune response may play an important role.3 In vitro studies have consistently shown that malignant cells in MF display tumor-specific antigens that can be recognized by autologous CD8+ CTLs.4-7 Taken together, these observations suggest that CD8+ CTLs are a critical component in the antitumor immune response in CTCL. However, studies that evaluate the number and immunophenotype of CD8+ CTLs in different stages of CTCL are scarce, and correlation with clinical behavior leads to contradicting results.8,9 CD8+ CTL–mediated tumor-cell lysis is achieved by at least two distinct pathways: (1) by exocytosis of intracytoplasmic granules that contain perforin, granzymes, and T cell–restricted intracellular antigen (TIA-1), and (2) by the Fas-mediated pathway in which membrane-bound Fas ligand (FasL) expressed on cytotoxic T cells interacts with Fas (CD95/Apo-1) on target cells.10,11 Both pathways activate a cascade of subcellular events that ultimately lead to the activation of caspases and target-cell death. The availability of monoclonal antibodies (MoAbs) against perforin, the serine proteases granzyme A and granzyme B (GrB), TIA-1, FasL, and Fas has enabled the study of these components involved in T cell–mediated cytotoxicity in tissue sections.12-15 Recently, killing inhibitory receptors (KIRs) were discovered as a new class of molecules that are able to modulate cytotoxic function of natural killer (NK) and T cells. At present, two groups of KIRs are known: the immunoglobulin (Ig) superfamily-like receptors (CD158a, CD158b)16 and the lectin-like receptors (CD94).17 These receptor molecules are expressed by subpopulations of NK cells and CD8+ CTLs. On ligation with MHC class I receptors on target cells, KIRs deliver inhibitory signals that impair cytolytic function.18 Thus, expression of KIRs by CTLs might impair their capacity to effectively kill virus-infected or tumor cells. Recent in vitro studies demonstrated the expression of functional KIRs on a CD8+, tumor-specific, cytotoxic, T-cell clone isolated from the peripheral blood of a patient with MF.19 However, studies of the expression of KIRs by cytotoxic cells in skin infiltrates of CTCL lesions have not yet been published, and the importance of the induction of KIRs as a mechanism to evade the immune response in CTCL is presently unknown. To further characterize the role of CD8+ CTLs in the antitumor immune response in CTCL, we investigated the proportions of CD8+ T cells and the expression of TIA-1, GrB, FasL, and KIRs by CD8+ CTLs in 83 initial biopsy samples from patients with plaque-stage MF (n = 42), tumor-stage MF (n = 20), and CD30- PCLTCL (n = 21) obtained at the time of diagnosis and 27 follow-up biopsy samples and correlated the results with clinical behavior.
Patients Eighty-three paraffin-embedded skin biopsy samples obtained at the time of diagnosis from 83 untreated CTCL patients, who included 62 MF patients and 21 CD30- PCLTCL patients, were studied. The diagnosis of MF and CD30- PCLTCL was based on a combination of clinical, histologic, and immunophenotypical data as described previously.1 The duration of skin lesions before a definite diagnosis could be made varied between 2 months and more than 10 years (median, 103 months) in MF and between 3 and 24 months (median, 12 months) in patients with CD30- PCLTCL. Only cases in which the neoplastic T cells had either a CD3+/CD4+/CD8- (n = 70) or a CD3+/CD4-/CD8- phenotype (n = 13) were included. Rare cases of MF and CD30- PCLTCL with a CD3+/CD4-/CD8+ phenotype were not selected for this study because it was impossible to make a reliable estimate of the number of reactive CD8+ T cells in these cases. Follow-up data, including response to initial therapy and survival, were recorded in each case (Table 1).
Of the 62 MF biopsy samples taken at the time of diagnosis, 42 were obtained from plaques from patients with generalized (T2N0M0) plaque-stage MF, and 20 were obtained from skin tumors from patients with tumor-stage MF without concurrent lymph node involvement (T3N0M0). For 19 of these 62 patients, 27 follow-up biopsy samples from plaques (n = 9) or skin tumors (n = 18) obtained at the time of relapse or disease progression 1 to 90 months (median, 24 months) after the first diagnostic biopsy were studied as well. The results of these biopsies are not included in the statistical analyses and will be discussed separately. Frozen sections obtained from the same excision biopsy sample or another biopsy sample from a similar concurrent lesion were used for KIR staining in 18 cases, including seven MF plaques, nine MF tumors, and two CD30- PCLTCL biopsy samples.
Immunohistochemistry Frozen sections. Snap-frozen specimens were stored in liquid nitrogen until use. NK cells were identified by their staining for CD56 (IgG1 subtype; Beckton and Dickinson, Poole, United Kingdom). Expression of KIR was studied using MoAbs against CD94 (IgG2 subtype), CD158a, and CD158b (Coulter Immunology), as described previously.25 Double staining for CD94 with CD56 or CD8 was performed in eight cases, which included three patients with MF plaques, three with MF tumors, and two with CD30- PCLTCL, by simultaneous incubation with primary antibodies followed by incubation with horseradish peroxidase–conjugated goat antimouse IgG1 and biotinylated goat antimouse IgG2a for the detection of CD56 or CD8 and CD94, respectively. The horseradish peroxidase was visualized by fluorescein-conjugated tyramine,26,27 whereas the biotin label was detected with cy3-conjugated streptavidin.
Interpretation of Immunohistochemical Staining
Statistical Analysis Univariate analysis of possible prognostic factors was performed using the log-rank test for categorical variables (stage) and Cox proportional regression analysis for continuous variables (percentage of CD8+ T cells, age). To assess independence of prognostic value, multivariate analysis was performed by entering the variables of interest in Cox proportional hazards regression analysis. Actuarial survival curves in MF were calculated from the time of the initial diagnostic biopsy until death from disease or end of follow-up using the Kaplan-Meier method. P values below .05 were considered statistically significant. All analyses were performed using Statistical Products and Services Solutions Software (SPSS Inc, Chicago, IL).
Percentage of CD8+ CTLs in CTCL The proportions of CD8+ CTLs in the MF and CD30-negative PCLTCL biopsy samples taken at the time of diagnosis are presented in Table 2. Major differences were found between MF plaques and tumors. Percentages of 20% or more CD8+ T cells were observed in 21 (50%) of 42 MF plaques but not in any of the 20 MF tumors. The median number of CD8+ T cells in MF was 17% (range, 2% to 50%). CD30- PCLTCL showed low percentages of CD8+ T cells, with a median value of 3% and less than 5% of CD8+ T cells in 12 (55%) of 21 cases. The differences in the proportions of CD8+ T cells between plaque-stage and tumor-stage MF and tumor-stage MF and CD30- PCLTCL were statistically significant (Student’s t test, P < .0001 and P = .018, respectively).
The results of the proportions of CD8+ T cells in 27 MF biopsy samples obtained during follow-up are summarized in Table 3. Taken together, the percentages of CD8+ T cells in nine MF plaques (median, 22%; range, 15% to 27%) and 18 MF tumors (mean, 10%; range, 2% to 17%) were similar to the percentages observed in plaques and tumors present at the time of diagnosis. Interestingly, examination of plaques in three MF patients who had concurrent tumors demonstrated high percentages of CD8+ T cells in the plaques (median, 25%) compared with the concurrent tumors (median, 10%; range, 7% to 15%).
Expression of Cytotoxic Proteins GrB, TIA-1, and FasL by CD8+ T Cells Expression of GrB, TIA-1, and FasL was detected as a clear, granular, cytoplasmic staining in all cases. Because a reliable estimation of the percentages of CD8+ T cells that express cytotoxic proteins might be hampered by the fact that these proteins are expressed not only by CD8+ CTLs but also by the neoplastic T cells of some types of CTCL28,29 and perhaps by rare reactive CD4+ T cells,30 double-staining experiments for CD8 with GrB or CD8 with TIA-1 were first performed in 10 cases, including four patients with MF plaques, four with MF tumors, and two with CD30- PCLTCL. These experiments demonstrated that TIA-1 and GrB are not or are rarely expressed by inflammatory cells other than CD8+ T cells (Fig 1). Moreover, because of the superior morphology in paraffin sections, the differentiation between CD8+ T cells and neoplastic T cells was generally not difficult. Examination of serial sections stained for CD8, GrB, TIA-1, and FasL showed a similar topographic distribution for CD8+ T cells and TIA-1+ and/or GrB+ cells. In plaque-stage MF, tumor-stage MF, and CD30- PCLTCL, most (60% to 90%) CD8+ T cells expressed TIA-1, whereas only a minority (generally less than 25%) of CD8+ T cells expressed GrB (Table 4; Fig 2). Staining for FasL showed granular intracytoplasmic staining in more then 50% of the CD8+ T cells in all but a few cases. Taken together, no significant differences in the relative proportions of CD8+ T cells that express TIA-1, GrB, or FasL were detected between MF plaques, MF tumors, and CD30- PCLTCL.
Expression of KIR by CD8+ T Cells To investigate whether the cytotoxic function of CD8+ T cells is possibly modulated by KIR, the expression of CD94, CD158a, and CD158b was studied. All antibodies demonstrated a membranous staining. CD94+, CD158a+, or CD158b+ cells comprised up to 5% of the total number of reactive cells. In all cases, the number of CD94+ cells was higher than the number of CD158b+ cells, which in turn outnumbered the CD158a+ cells. No differences were observed in the number of reactive cells that expressed CD94, CD158a, and CD158b between MF plaques, MF tumors, and CD30- PCLTCL. Double-staining experiments for CD56 or CD8 with CD94 demonstrated coexpression of CD56 with CD94 in more than 95% of CD94+ cells, whereas colocalization of CD8 with CD94 was limited to a few scattered cells (Fig 3).
Correlation of CD8+ T Cells With Clinical Characteristics Cox proportional hazards regression analysis in the total group of 62 MF patients demonstrated that survival in MF patients declined with lower numbers of CD8+ T cells (P = .001). Also, within tumor-stage MF, high numbers of CD8+ T cells correlated with an increased survival (P = .003). In plaque-stage MF, the relation between the percentages of CD8+ T cells and survival did not reach significance, although a trend was observed toward a better survival in patients with higher numbers of CD8+ T cells. Univariate analysis demonstrated that stage of disease (P = .0004) and the percentage of CD8+ T cells (P = .001) but not age (P = .57) correlated with survival. Multivariate analysis showed that both stage of disease and the number of CD8+ T cells were independent prognostic parameters. The actuarial survival curves for all MF patients divided the patients into two groups using the median number of CD8+ T cells (17%) as the cutoff point (Fig 4).
In the present study, the expression of cytotoxic proteins by CD8+ T cells and the relation between the percentages of CD8+ T cells and clinical behavior was studied in MF and CD30- PCLTCL. We demonstrated that, in all types of CTCL, the large majority of CD8+ T cells expressed TIA-1 and FasL, whereas a minority was GrB positive. These results are consistent with the results of a previous study that demonstrated that the majority of CD8+ T cells expressed TIA-1 but not granzymes.31 Similarly, the neoplastic cells in CD8+ epidermotropic cytotoxic T-cell lymphomas, which may be considered the neoplastic equivalents of these reactive CD8+ cytotoxic T cells, also showed constant expression of TIA-1 but rarely expressed GrB or perforin.32 With respect to the cytotoxic phenotype of these CD8+ T cells, in vitro studies demonstrated that, although TIA-1 is expressed on both resting and activated CTLs,33 perforins and granzymes are only expressed after activation34 and might therefore be a more reliable marker for activated CTLs. Because TIA-1 was expressed by most CD8+ T cells and GrB was expressed by only a minority of these cells (5% to 10%) in all groups studied, one may wonder whether these cells are functionally active CTLs. One possible explanation for the low GrB expression is that most CD8+ T cells had already secreted their GrB as has been demonstrated in skin biopsy samples of lichen planus.35 Interestingly, recent studies of our group demonstrated that, in skin biopsy samples of lichen planus, lupus erythematosus, and graft-versus-host disease, the majority of CD8+ T cells expressed TIA-1, whereas GrB was expressed by only a small number of these cells (unpublished data). Epidermal injury and apoptotic keratinocytes were a constant finding in these biopsy samples, illustrating the presence of functionally active CTLs. Thus, these findings illustrated that the low expression of GrB compared with TIA-1 by the CD8+ T cells in these CTCLs does not exclude the possibility that they are functionally active CTLs directed at the neoplastic T cells. Tumor cells use various escape mechanisms to evade an effective antitumor response. Recent studies of our group demonstrated that the loss of Fas expression by the neoplastic cells in aggressive types of CTCL may be one of these mechanisms.36 Another mechanism to evade the immune response may be the inhibition of cytolytic function through KIRs. Expression of KIRs was demonstrated on tumor-specific CD8+ CTLs in melanoma patients, and functional studies showed that tumor-specific lysis was inhibited by these KIRs.37 Recent in vitro studies demonstrated the expression of functional KIRs on a CD8+ tumor-specific cytotoxic T-cell clone isolated from the peripheral blood of an MF patient.19 Whether the in vitro expansion of T cells may lead to the induction of KIRs is presently unknown. In the present study, KIRs were expressed only by a few scattered NK cells but never or rarely by CD8+ T cells, which argues against a role for these KIRs in tumor progression in CTCL. Correlation of the percentages of CD8+ CTLs and clinical behavior in MF and CD30- PCLTCL showed that the proportions of CD8+ CTLs were significantly higher in MF plaques than in MF tumors, which in turn outnumbered the percentages of CD8+ T cells in CD30- PCLTCL. The decline in the percentage of CD8+ CTLs was associated with a less favorable prognosis. Also, within tumor-stage MF, a relation between higher percentages of CD8+ CTLs and better survival was found. Multivariate analysis demonstrated that both skin stage and the proportion of CD8+ T cells were independent parameters of survival. Examination of 27 additional follow-up skin biopsy samples of MF patients showed similar percentages of CD8+ CTLs in plaques and tumors when compared with plaques and tumors biopsied at the time of diagnosis. Interestingly, MF plaques in patients who had concurrent skin tumors contained considerable proportions of CD8+ CTLs (median, 25% v 10% in the concurrent tumors), as seen in MF patients with plaque lesions only. Taken together, these observations suggest that, in patients who have already progressed to tumor-stage MF, an effective antitumor response is still functioning in concurrent MF plaques that prevents tumor progression at those sites. Previous studies that address the relation between the proportions of CD8+ CTLs and clinical behavior in CTCL are few, have mainly been focused on MF, and have reached conflicting conclusions.8,9 Consistent with our results, Hoppe et al9 also described a relation between high proportions of CD8+ CTLs and a better survival in MF. However, no statistically significant difference in the percentage of CD8+ CTLs between MF plaques and tumors was found. In contrast, in a study by Vonderheid et al,8 the percentages of CD8+ CTLs decreased from 11.9% to 6.4% to 3.8% in MF patches, plaques, and tumors, respectively, but no relation between the percentages of CD8+ CTLs and survival was found in this study. In the group of CD30- PCLTCL, characterized by an extremely poor prognosis, low percentages of CD8+ CTLs (median, 3%) were found. Taken together, high proportions of CD8+ CTLs were found in the patient group with a favorable prognosis (plaque-stage MF) and low proportions of CD8+ CTLs in groups with a poor prognosis (tumor-stage MF, CD30- PCLTCL), which suggests that CD8+ CTLs play an important role in the antitumor immune response in CTCL. This notion is in line with earlier studies that demonstrated that malignant cells in MF express tumor-specific antigens that can be recognized by autologous CD8+ CTLs in vitro.4-6 In conclusion, we demonstrated that reactive CD8+ T cells in CTCL had the phenotype of partly activated cytotoxic T cells (TIA-1+, GrB-/+, FasL+) but did not express KIRs. Moreover, we demonstrated that high percentages of infiltrating CD8+ CTLs were associated with a better prognosis. Taken together, these observations suggest that CD8+ CTLs could play an important role in the antitumor response in CTCL.
We thank Els de Vries and Wim Vos for their excellent technical assistance.
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van Doorn R, Van Haselen CW, van Voorst-Vader PC, et al: Mycosis fungoides disease evolution and prognosis of 309 Dutch patients. Arch Dermatol 136: 504-510, 2000 3. Rook AH, Yoo EK, Grossman DJ, et al: Use of biological response modifiers in the treatment of cutaneous T-cell lymphoma. Curr Opin Oncol 10: 170-174, 1998[Medline] 4. Berger CL, Wang N, Christensen I, et al: The immune response to class I-associated tumor-specific cutaneous T-cell lymphoma antigens. J Invest Dermatol 107: 392-397, 1996[Medline] 5. Berger CL, Longley BJ, Imaeda S, et al: Tumor-specific peptides in cutaneous T-cell lymphoma: Association with class I major histocompatibility complex and possible derivation from the clonotypic T-cell receptor. Int J Cancer 76: 304-311, 1998[Medline] 6. Bagot M, Echchakir H, Mami-Chouaib F, et al: Isolation of tumor-specific cytotoxic CD4+ and CD4+ CD8dim+ T-cell clones infiltrating a cutaneous T-cell lymphoma. Blood 11: 4331-4341, 1998 7. Echchakir H, Bagot M, Dorothee G, et al: Cutaneous T-cell lymphoma reactive CD4+ cytotoxic T lymphocyte clones display a Th1 cytokine profile and use a fas-independent pathway for specific tumor cell lysis. J Invest Dermatol 115: 74-80, 2000[Medline] 8. Vonderheid EC, Tan E, Sobel EL, et al: Clinical implications of immunologic phenotyping in cutaneous T-cell lymphoma. J Am Acad Dermatol 17: 40-52, 1987[Medline] 9. Hoppe RT, Medeiros LJ, Warnke R, et al: CD8-positive tumor-infiltrating lymphocytes influence the long-term survival of patients with mycosis fungoides. J Am Acad Dermatol 32: 448-453, 1995[Medline]
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Mingari MC, Schiavetti F, Ponte M, et al: Human CD8+ T lymphocyte subsets that express HLA I-specific inhibitory receptors represent oligoclonally or monoclonally expanded cell populations. Proc Nat Acad Science 93: 12433-12438, 1996 19. Bagot M, Martinvallet H, Echchakir H, et al: Functional inhibitory receptors expressed by a cutaneous T cell lymphoma-specific cytolytic clonal T cell population. J Invest Dermatal 115: 994-999, 2000[Medline] 20. Kummer JA, Kamp AM, van Katwijk M, et al: Production and characterization of monoclonal antibodies raised against recombinant human granzymes A and B showing cross reactions with the natural proteins. J Immunol Methods 163: 77-83, 1993[Medline] 21. Kummer JA, Kamp AM, Tadema TM, et al: Localization and identification of granzymes A- and B-expressing cells in normal human lymphoid tissue and peripheral blood. Clin Exp Immunol 100: 164-172, 1995[Medline] 22. Oudejans JJ, Kummer JA, Jiwa NM, et al: Granzyme B expression in Reed-Sternberg cells of Hodgkin’s disease. Am J Pathol 148: 233-240, 1996[Abstract] 23. Zoi-Toli O, Meijer CJLM, Oudejans JJ, et al: Prognostic significance of Fas and Fas-ligand expression in cutaneous B-cell lymphomas. J Pathol 189: 533-538, 1999[Medline]
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
