Research Report 2010 - MDC

CXCR5 drives the development of ectopic follicles in the gastric mucosa inH. pylori-infected mice. Histological analysis of paraffin embedded stomachsof CXCR5 -/- compared to wild type mice 5-6 month after H. pyloriinfection showed that ectopic follicles do not develop in CXCR5 -/- mice.MALT-lymphoma and gastric cancer in in vivo mousemodels.Immunosurveillance and interactions betweentumor cells and its microenvironmentIdentification of a chemokine receptor profile characteristicfor mediastinal large B-cell lymphoma (MLBCL)in cooperation with A. Rehm, I. Anagnostopoulos, H. Stein,and B. Dörken, MDC, Charité, BerlinWe have shown that the most frequent lymphomaentities involving the mediastinum can be diagnosedbased on the combination of five different homeostaticchemokine receptor stainings. In contrast to diffuselarge B cell lymphoma (DLBCLnos) and classicalHodgkin lymphoma, MLBCLs are largely devoid of thehomeostatic chemokine receptors CXCR5 and CCR7, andalso lack CCR6. These findings suggest that extranodallocalization and lack of nodal dissemination in MLBCLare related to the expression of those lymph nodeaddressins. Conversely, expression of these receptors onessentially all B cell neoplasms with a widespread nodaldissemination provide a rationale for the therapeutictargeting of homeostatic chemokine receptors withantibodies or antagonistic compounds.Cellular interactions between lymphoma cells andtheir accessory or tumor stroma cellsin cooperation with A. Rehm, and B. Dörken, MDC, Charité,BerlinBased on our phenotypical analysis of chemokine/chemokine receptor expression in MLBCL, we now focuson the cellular interactions between lymphoma cellsand their accessory or tumor stroma cells. Investi gat -ions on the relationship between lymphoma cells andits local immune environment includes the analysis ofactive immune escape mechanisms in murine B celllymphoma. We backcrossed the transgenic malignantlymphoma mouse strain, Eµ-Myc, onto diversechemokine receptor KO strains, which will help to decipherthe influence of tumor cell homing within a specificlymph node and splenic niche onto disease onsetand progression. A more profound understanding ofmechanisms that may cause non-Hodgkin lymphomato be addicted to the local microenvironment could providenew targets for therapeutic intervention.Immunoregulatory functions of the tumorassociatedantigen EBAG9/RCAS1in cooperation with A. Rehm, and B. Dörken, MDC, Charité,BerlinThis project studies whether the estrogen-inducibletumor-associated antigen, EBAG9, has a concurrentimpact on T cell-mediated tumor immunosurveillance.Cytotoxic T lymphocytes (CTL) are essential forimmuno surveillance and score cells for the display oftumor-derived peptides. For target cell destruction, CTLsemploy polarized secretion of lytic granules. We generatedEBAG9 knockout mice and characterized the consequencesof its deletion in CTL-mediated immuneresponses. Loss of EBAG9 amplifies the release of lyticgranules and confers CTLs with an enhanced cytolyticactivity, in all likelihood through improved formation offusion- and release-competent secretory lysososomes.With regard to tumor immunosurveillance and tumorimmunotherapy, modulating the cell biological roadblocksin T cell activation and cytolytic capacity on a singlecell level emerges as a strategy to increase avidityand to strengthen anti tumor T cell efficiency. Our identificationof the estrogen tunable repressor of cytotoxicT cell activity, EBAG9, will allow us to suppress its activitythrough pharmacological estrogen receptor blockade.Selected PublicationsHöpken, UE, Winter, S, Achtman, AH, Krüger, K, Lipp, M. (2010). CCR7regulates lymphocyte egress and recirculation through body cavities.J. Leukoc. Biol. In press.van de Pavert SA, Goverse G, Vondenhoff MF, Beke P, Höpken UE, Lipp M,Niederreither K, Blomhoff R, Agace WW, Mebius R (2009): CXCL13 is essentialfor lymph node initiation and is induced by retinoic acid and neuronalstimulation. Nature Immunology 10, 1193-1199.Rüder, C, Höpken, UE*, Wolf, J, Mittrücker, H-W, Engels, B, Erdmann, B,Wollenzin, S, Uckert, W, Dörken, B, Rehm, A*. (2009). The tumor-associatedantigen EBAG9 negatively regulates the cytolytic capacity of mouseCD8+ T cell. J. Clin. Invest. 119: 2184-2203*shared corresponding authorRehm, A, Anagnostopoulos, I, Gerlach, K, Broemer, M, Scheidereit, C,Jöhrens, K, Hübler, M, Stein, H, Lipp, M, Dörken, B, Höpken, UE. (2009).Identification of a chemokine receptor profile characteristic for mediastinallarge B-cell lymphoma. Int. J. Cancer 125, 2367-2374Höpken, UE, Wengner, AM, Loddenkemper, C, Stein, H, Heimesaat, MM,Rehm, A, Lipp, M. (2007). CCR7 Deficiency causes ectopic lymphoidneogenesis and disturbed mucosal tissue integrity. Blood 109, 886-95.Cancer Research 121