Die prognostische Bedeutung von Lymphom-infiltrierenden Zellen der Immunabwehr bei mit Rituximab behandelten follikulären Lymphomen

Patients with Follicular Lymphoma show great differences in the progression, response to therapy and survival, whereas the tumor grading and the Follicular Lymphoma Prognostic Index (FLIPI) do not always correlate unambiguously with the prognosis. A promising predicting factor could be found in the examination of the microenvironment, the tumor infiltrating cells of the immune system. The supposition, that the follicular lymphoma can be viewed as an immunological disease, in which the interaction between tumor-cells and bystander-cells give distinction to the clinical features, is generally accepted. Tumor-infiltrating T-Lymphocytes as well as dendritic cells is ascribed a positive, macrophages a negative prognostic effect. The antibody Rituximab was able to prove its thera-peutic value in treatment of follicular lymphoma in multiple studies. Direct induc-tion of apoptosis, complement mediated lysis and antibody dependent cellular cytotoxicity play a role in its mode of operation. Purpose: This thesis was conducted following up on a study which Herold at al published in 2007, showing the positive prognostic impact of the CD20-antibody Rituximab in comparison to exclusively applied chemotherapy in treatment of patients with follicular lymphoma. Our purpose was to investigate whether the significance of specific bystander-cells is influenced by Rituximab in a uniformly chemotherapeutically treated cohort. Methods: With help of immunohistochemical staining of specific surface anti-gens of T-, natural killer (NK)- and dendritic cells, monocytes, the intracellular protein Ski, PLCγ and ZAP70 we were able to quantify the cells by a computer-ized method. For each antigen, the 18 investigated patients were subdivided into groups by the amount of infiltrating cells (high/low) and, regarding the location of the cells (intra-/extrafollicular), the progression free survival was investigated. Results: Investigation of the amount of infiltrating bystander cells alone showed no significant difference in prognosis. In correlation with the Rituximab-therapy however the expression of some antigens could be associated with prolonged PFS and we were able to detect certain patterns: Patients with infiltration patterns, which were priorly described in literature as having an adverse effect on prognosis, particularly benefitted from therapy with the CD20-antibody. PFS of patients with low amounts of intrafollicular T-Cells in the Rituximab-cohort was significantly increased (identified by CD3 (p=0,0221), CD8 (p=0,0500) und ZAP70 (p= 0,0401)). Furthermore, patients with high counts of macrophages showed prolonged PFS under therapy with Rituximab (p=0,0419). Hence it may be presumed, that an additional therapy with Rituxi-mab can overcome the prognostic disadvantage of patients with above men-tioned infiltration patterns, or respectively, that the therapeutic effect shows more distinctly with those patients. Furthermore a high amount of extrafollicular NK-cells (identified by CD56) was associated with longer PFS in the Rituximab-cohort, which can possibly be ex-plained by an increased antibody dependent cellular cytotoxicity to develop the therapeutic effect. Concerning the prime object of the CD20-antibody, PFS under Rituximab-therapy was prolonged in the subgroup with low counts of infiltrating CD20-positive cells in the extrafollicular region (p=0,0328). This could possibly lead to the conclusion that a higher dose of the antibody might be needed to reach the b-cells in the center of the follicle in patients with high extrafollicular CD20-cell-counts. Perspective: Especially under therapy with Rituximab, the close investigation of tumor infiltrating bystander-cells of the immune system also seems to hold an important prognostic value. The results of this study should however be validated by further investigations within a larger, uniformly treated collective.