Blood, Vol. 90 No. 9 (November 1), 1997:
pp. 3810-3810
CORRESPONDENCE
Granzyme A mRNA Expression in Mycosis Fungoides Progression
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LETTER |
To the Editor:
In a recent issue of Blood, Oudejans et al1 showed the presence of CD8+, granzyme B+ lymphocytes, considered to be activated cytotoxic T cells, in Hodgkin's disease. Interestingly, the presence of a high percentage of granzyme B+ lymphocytes was found to be an unfavorable prognostic marker. This is surprising because cytotoxic lymphocytes mediated lysis of tumor cells, predominantly achieved by perforine and granzymes, is considered to be of major importance for antitumor response.2 Oudejans et al suggested that their findings reflects an inability of activated cytotoxic T lymphocytes to kill the malignant Hodgkin's Reed-Sternberg cells. They speculated that certain cytokines, mainly interleukin-10 (IL-10), known to be produced by the malignant cell, could be responsible for this phenomenon, as it may induce a local T-cell anergy.
We have very recently shown IL-10 overexpression in mycosis fungoides (MF ), a frequent cutaneous T-cell lymphoma.3 Although there is evidence for a local4 and a systemic antitumor cell-mediated immune response,5 granzyme A mRNA expression was studied only in MF skin samples by in situ hybridization and was not detected.6 Therefore, we investigated whether cutaneous granzyme A mRNA is detectable in this non-Hodgkin's lymphoma, by using a sensitive competitive reverse transcriptase-polymerase chain reaction (RT-PCR) technique as recently described.3
Granzyme A mRNA was detectable in all cutaneous T-cell lymphoma skin samples. A stage-dependent increase of granzyme A mRNA expression was detected (Table 1). Remarkably, correlation with a stage-dependent increase of IL-10 mRNA levels was found (r = .645, P = .003). Moreover, in parallel an increase of CD3 mRNA expression, indicating increasing T-cell infiltration, was observed (Table 1).
Our findings indicate that the presence of granzyme, a marker of activated cytotoxic T lymphocytes (CTL)/natural killer cells, in lymphoma is not restricted to Hodgkin's disease. Moreover, similar to the findings in Hodgkin's disease, granzyme expression seems to be a negative prognostic sign in MF, because a stage-dependent increase was found and advanced stages are kown to have a less favorable prognosis than early stages.7 Finally, the concomittant increase of cutaneous IL-10 and granzyme A mRNA levels further support the hypothesis by Oudejans et al that this cytokine may be involved in the development of some kind of CTL resistence at the side of the tumor.
In contrast to Oudejans, who performed immunohistological double-staining experiments, we could not conclude from our mRNA data that CD8+ cytotoxic T cells are the source of the granzyme expression in non-Hodgkin's lymphoma, although a T-cell source may be suggested because the CD3 mRNA levels rised in parallel. Moreover, it has been reported on the poor prognosis of granzyme B-expressing peripheral T-cell lymphomas.8 Remarkably, MF progression is often characterized by increasing numbers of malignant CD4 but decreasing CD8+ T cells in the skin lesions. Therefore, the increasing granzyme levels we found may reflect such a shift in the cellular pattern of the T-cell infiltrate, if the malignant MF cell could produce granzyme. Such a scenario would be of major importance, because it may indicate the capacity of the malignant cells to induce apoptosis in antitumor immune cells and escape from immune control. Therefore, further investigations to clarify these observations should be performed.
Khusru Asadullah
Markus Friedrich
Antje Haeu
ler
Wolfram Sterry
Department of Dermatology
Wolf-Dietrich Döcke
Hans-Dieter Volk
Department of Medical Immunology
University Hospital Charité
Berlin Humboldt University
Berlin, Germany
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ACKNOWLEDGMENT |
Supported by a grant from the Deutsche Forschungs Gemeinschaft (Ste 366/7-1).
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REFERENCES |
1.
Oudejans JJ,
Jiwa NM,
Kummer JA,
Ossenkoppele GJ,
van Heerde P,
Baars JW,
Kluin PhM,
Kluin-Nelemans JC,
van Diest PJ,
Middeldorp JM,
Meijer CJLM:
Activated cytotoxic T cells as prognostic marker in Hodgkin's disease.
Blood
89:1376,
1997[Abstract/Free Full Text]
2.
Smyth MJ,
Trapani JA:
Granzymes: Exogenous proteinases that induce target cell apoptosis.
Immunol Today
16:202,
1995[Medline]
[Order article via Infotrieve]
3.
Asadullah K,
Döcke WD,
Haeuler A,
Sterry W,
Volk HD:
Progression of mycosis fungoides is associated with increasing cutaneous expression of IL-10 mRNA.
J Invest Dermatol
107:833,
1996[Medline]
[Order article via Infotrieve]
4.
Hoppe RT,
Medeiros LJ,
Warnke RA,
Wood GS:
CD8-positive tumor-infiltrating lymphocytes influence the long-term survival of patients with mycosis fungoides.
J Am Acad Dermatol
32:448,
1995[Medline]
[Order article via Infotrieve]
5.
Asadullah K,
Friedrich F,
Döcke WD,
Jahn S,
Volk HD,
Sterry W:
Enhanced expression of T-cell activation and natural killer cell antigens indicates systemic anti-tumor response in early primary cutaneous T cell lymphoma.
J Invest Derm
108:743,
1997[Medline]
[Order article via Infotrieve]
6.
Wood GS,
Dubiel C,
Mueller C,
Abel EA,
Hoppe RT,
Edinger A,
Weissman I,
Warnke RA:
Most CD8+ cells in skin lesions of CD3+ CD4+ mycosis fungoides are CD3+ T cells that lack CD11b, CD16, CD56, CD57, and human hanukah factor mRNA.
Am J Pathol
138:1545,
1991[Abstract]
7.
Lorincz AL:
Cutaneous T-cell lymphoma (mycosis fungoides).
Lancet
347:871,
1996[Medline]
[Order article via Infotrieve]
8.
De Bruin PC,
Kummer JA,
van der Valk P,
van Heerde P,
Kluin PM,
Willemze R,
Ossenkoppele GJ,
Radaszkiewicz T,
Meijer CJLM:
Granzyme B-expressing peripheral T-cell lymphomas: Neoplastic equivalents of activated cytotoxic T cells with preference for mucosa-associated lymphoid tissue localization.
Blood
84:3785,
1994[Abstract/Free Full Text]
