Page 124 - Haematologica3

F. Knörr et al.
of cytokine-signature for ALK-positive ALCL when com- pared with those of both remission samples and samples from age-matched children with low-stage B-cell non- Hodgkin lymphoma as separate controls.
The concentrations of sIL-2R and sCD30 were expect- edly higher in ALCL patients than in controls since ALCL cells, by definition, express CD30 and show strong stain- ing for CD25, the α-subunit of the IL-2 receptor.12-14,21 Both molecules can be shed by the tumor cells.12,22 The detection of IL-9 would be in accordance with the previously described autocrine IL-9/JAK3 signaling in ALCL.15 ALCL cells have been described to resemble a Th17 phenotype and to produce IL-17.9,23 Cumulatively, these data suggest that these elevated serum cytokines might be produced by the lymphoma.
Within the cohort of patients with ALK-positive ALCL, high levels of IL-6, IFN-γ, IP-10, and sIL-2R correlated with high stage, initial poor general condition, minimal disseminated disease, low ALK-antibody titers, and lower event-free survival at 3 years. The concentrations of sIL-2R and IL-6 correlate with the extent of disease, relapse risk and survival in different tumor types includ- ing Hodgkin lymphoma and peripheral T-cell lymphoma.24-27 The levels of sIL-2R, sCD30 and IL-6 have been described as independent prognostic markers in both Hodgkin lymphoma patients and patients with peripheral T-cell lymphoma.8,27,28 Several strong inde- pendent biological prognostic parameters are available in patients with ALK-positive ALCL.29 It is not, therefore, unexpected that only IL-6 retained an independent prog- nostic value for event-free survival in our cohort of ALK- positive ALCL patients in a multivariate analysis includ- ing the established risk factors, minimal disseminated disease and anti-ALK antibody titers.18-20
sIL-2R was described as a marker of disease activity in a cohort of nine ALK-negative and ALK-positive ALCL patients evaluated at different time points.12 As for sIL-2R, higher levels of sCD30 were associated with higher stage, presence of minimal disseminated disease and other clini- cal characteristics in our cohort. These findings support a role of sCD30 and sIL-2R as markers of tumor burden.25
The cumulative observations that IL-23 levels correlated directly with the anti-ALK antibody titers in our study and that this cytokine has been shown to be produced by acti- vated dendritic cells,30 is involved in Th17 effector func- tions31 and has a role in autoimmunity32 might suggest that
IL-23 could support the production of autoantibodies. Elevated concentrations of IL-10 were correlated with minimal disseminated disease positivity, disease stage and significantly lower event-free survival at 3 years in uni- variate analyses and could hint toward an immune eva- sion of the tumor. ALK-positive ALCL express PD-L1,33 involved in suppression of the immune response, and IL- 10-secretion in ALK-positive ALCL is induced via STAT3 signaling.34 Elevated concentrations of IL-10 may reflect immune evasion of the tumor and suppression of cytotox-
ic T-cell functions.
We also investigated whether a Th-subset-specific
serum cytokine pattern could be identified in ALCL patients. Although some patients showed a pattern of ele- vated IFN-γ, IP-10 and MIG (these latter two both pro- duced upon stimulation with IFN-γ35) and levels of IL-17 and IL-23 might hint towards the activation of Th17 cells, the majority of ALCL patients did not show a conclusive pattern. The concept of a certain Th response linked to a disease has been questioned by the discovery of a plethora of newly described subsets and the plasticity of those cell types.36 In addition, a multitude of host factors, tumor dis- semination and individual tumor characteristics could influence the cytokine expression pattern.
In summary, our findings suggest that expression of IL- 9, IL-10, IL-17a, HGF, sIL-2R, and sCD30 form a cytokine signature typical of ALK-positive ALCL. The levels of IL- 6, IFN-γ, IP-10, and sIL-2R correlated with lymphoma dis- semination, other poor prognostic factors and the risk of relapse among pediatric patients with ALK-positive ALCL. Our data underline the role of immune mediators in explaining part of the typical clinical presentation of ALCL patients with B symptoms and further signs of systemic inflammation. IL-6, as a classical cytokine marker of inflammation, was also an independent prognostic param- eter. More work is needed to elucidate the role of the cel- lular immune response to ALK-positive ALCL and to understand the role of mediators in the tumor microenvi- ronment in patients.
Acknowledgments
This work was supported by a grant from the Deutsche José Carreras Leukämie-Stiftung (DJCLS08/09) to WW. FK, CDW and WW were additionally supported by Forschungshilfe Peiper.
We wish to thank J. Schieferstein and S. Schwalm for their expert technical assistance.
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