Percentage of activated cytotoxic T-lymphocytes in anaplastic large cell lymphoma and Hodgkin's disease: an independent biological prognostic marker

Abstract

Recently, we demonstrated that the presence of high percentages of activated cytotoxic T-lymphocytes (CTLs) in biopsy specimens of both Hodgkin's disease (HD) and ALK negative anaplastic large cell lymphoma (ALCL) is associated with a poor prognosis. To test whether this biological prognostic factor is more important in predicting clinical outcome than histological diagnosis or clinical factors, we compared the prognostic value of these parameters in an expanded group of classical HD and ALK negative ALCL. Tumor biopsies of classical HD (n = 83) and ALK negative systemic nodal ALCL (n = 43) were investigated for the presence of activated CTLs by immunohistochemistry, using a monoclonal antibody directed against granzyme B. Percentages of activated CTLs were quantified using Q-PRODIT, and their prognostic value was compared to that of histological diagnosis and clinical parameters, including age and stage. Both in classical HD and ALK negative ALCL, a high percentage of activated CTLs (ie у15%) identified a group of patients with poor overall and progression-free survival time, even when adjusted for stage. In multivariate analysis, percentage of activated CTLs remained a strong independent prognostic marker, and was more sensitive than histological diagnosis or clinical factors in predicting overall survival time. We conclude that a high percentage of activated CTLs in the reactive infiltrate of ALK negative ALCL and classical HD is a strong indicator for an unfavorable clinical outcome, regardless of histological diagnosis or clinical parameters. As such, this biological parameter may be an especially helpful tool to determine therapeutic strategies in cases in which the differentiation between ALK negative ALCL and HD remains difficult. Leukemia (2001) 15, 458-464.

A molecular risk score based on 4 functional pathways for advanced classical Hodgkin lymphoma

“…Small molecule inhibitors of the Bcl-2 family have demonstrated high target affinity and an improved toxicity profile, and clinical trials of these agents are yielding interesting results. 35 Confirming previous observations about the importance of the reactive microenvironment for cHL patient outcome, 9,11,12 LYZ and STAT1 genes, expressed at high levels in a subset of tissue monocytes and activated macrophages, also are included in this model, and correlated with prolonged FFS and better outcome. The relevance of the cell composition of the reactive background in cHL has been reinforced by the data recently reported by Steidl et al 36 They used gene expression profiling to identify a gene signature of tumor-associated macrophages that is associated with treatment failure, in an approach methodologically similar to previous reports from our group and others.…”

“…4 The clinical outcome of cHL has been found to be related to the expression of multiple biologic markers alone [5][6][7][8] or in combination, 9 expressed either by the tumor HRS cells, macrophages, regulatory T cells, or other nonneoplastic cell subpopulations. [10][11][12][13] Some of these previous analyses rely on array-based gene expression analyses, which use frozen tissue and in most cases can only provide retrospective information. Investigators of other studies have used immunohistochemical staining, with some inherent limitations to the reproducibility of the data thus generated.…”

Tumor microenvironment and mitotic checkpoint are key factors in the outcome of classic Hodgkin lymphoma

“…As a result, we identified clusters of functionally related genes that are associated with clinical outcome and are expressed by either the reactive cell component or the neoplastic H/RS cells. HL is the prototype of lymphoma in which survival and progression have been traditionally associated with the immune response, 36,37 and many recent studies also suggest the importance of the microenvironment in outcome prediction in other tumors, 24,38 underscoring the necessity of gene expression analysis using RNA extracted from whole-tissue samples.…”

“…Thus, the first half of the genes reflect specific cell populations that participate in particular immune responses, some of which had been previously reported as modifiers of the clinical outcome (eg, cytotoxic T-cell response 37,39 together with the expression of macrophage markers such as LYZ and ALDH1A1, is suggestive of an important role of tumorassociated macrophages. Macrophages infiltrated into a tumor have a complex, ambivalent relationship with cancer cells and can suppress local T-cell-mediated immune response through a STAT1-dependent mechanism, resulting in the inhibition of antitumor immunity and the promotion of tumor progression.…”

Macrophages predict treatment outcome in Hodgkin's lymphoma

“…In HL, several biomarkers other than CD68 have been reported to be associated with treatment outcome, in particular markers expressed by certain T-cell subsets. [21][22][23][24] It, therefore, appears to be a logical next step to explore whether multi-gene predictors combining different markers can exceed the performance of individual biomarkers alone with the aim of better outcome prediction following primary treatment in HL. This approach was already tried in some studies using low-density gene expression techniques 12,13 or genomewide gene-expression profiling, developing predictors for favorable and unfavorable treatment outcome.…”