Marcus Lettau

University Hospital Schleswig-Holstein

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Trends

Author Order

Document Type

Co-Authors

Ottmar Janßen

University Hospital Schleswig-Holstein

Dieter Kabelitz

University Hospital Schleswig-Holstein

Guranda Chitadze

University Hospital Schleswig-Holstein

Daniela Wesch

University Hospital Schleswig-Holstein

Christian Peters

University Hospital Schleswig-Holstein

Hans‐Heinrich Oberg

Kiel University

Matthias Leippe

Kiel University

Matthias Voß

Kiel University

Christoph Gelhaus

Kiel University

Hendrik Schmidt

University of Lübeck

Cooperative Institutions

Kiel University

University of Lübeck

University Hospital Schleswig-Holstein

Clinical Research Center Kiel

Heidelberg University

Institute of Immunology

University of Cologne

Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases

University Hospital Cologne

German Cancer Research Center

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Field

NKG2D- and T-cell receptor-dependent lysis of malignant glioma cell lines by human γδ T cells: Modulation by temozolomide and A disintegrin and metalloproteases 10 and 17 inhibitors

OncoImmunology (2015)

Guranda Chitadze Marcus Lettau Stefanie Luecke Ting Wang Ottmar Janßen

The interaction of the MHC class I-related chain molecules A and B (MICA and MICB) and UL-16 binding protein (ULBP) family members expressed on tumor cells with the corresponding NKG2D receptor triggers cytotoxic effector functions in NK cells and γδ T cells. However, as a mechanism of tumor immune escape, NKG2D ligands (NKG2DLs) can be released from the cell surface. In this study, we investigated the NKG2DL system in different human glioblastoma (GBM) cell lines, the most lethal brain tumor in adults. Flow cytometric analysis and ELISA revealed that despite the expression of various NKG2DLs only ULBP2 is released as a soluble protein via the proteolytic activity of "a disintegrin and metalloproteases" (ADAM) 10 and 17. Moreover, we report that temozolomide (TMZ), a chemotherapeutic agent in clinical use for the treatment of GBM, increases the cell surface expression of NKG2DLs and sensitizes GBM cells to γδ T cell-mediated lysis. Both NKG2D and the T-cell receptor (TCR) are involved. The cytotoxic activity of γδ T cells toward GBM cells is strongly enhanced in a TCR-dependent manner by stimulation with pyrophosphate antigens. These data clearly demonstrate the complexity of mechanisms regulating NKG2DL expression in GBM cells and further show that treatment with TMZ can increase the immunogenicity of GBM. Thus, TMZ might enhance the potential of the adoptive transfer of ex vivo expanded γδ T cells for the treatment of malignant glioblastoma.

NKG2D

Temozolomide

10.1080/2162402x.2015.1093276

Cite

Citations (60)

FasL associated factors and their potential role in the regulation of FasL expression

Signal Transduction (2005)

Jing Qian Marcus Lettau Graziella Podda Ottmar Janßen

Fas Ligand (FasL) is a death factor with multiple functions. The expression and release of FasL is tightly regulated at a post-transcriptional level by sorting of FasL in so-called secretory lysosomes or directly on the cell membrane. The underlying mechanism and protein-protein interactions involved are largely unknown. Three putatively ‘FasL associated factors’ (FLAF1-3) had been identified earlier in a yeast two-hybrid screen by using the cytoplasmic portion of FasL as bait. Until today, nothing is known about their role in the context of FasL expression and function. Here we show that FLAFs interact with FasL via SH3 or WW domain binding to the proline-rich domain in the cytosolic tail of FasL. FLAF1 forms part of the formin binding protein 11 (FBP11, also called huntingtin-interacting protein A, HYPA), FLAF2 is part of the c-Cbl-associated protein SH3P12 = “sorbin and SH3 domain containing 1” and FLAF3 represents a portion of the BAI1-associated protein 2 (BAP2β). SH3P12 and BAP2β could precipitate FasL in double transfectants. The interaction of SH3P12/FasL and BAP2β/FasL results in the enhanced surface expression of FasL. These findings suggest that in contrast to other FasL interacting proteins, SH3P12 and BAP2β do not target FasL to the lysosomal compartment but rather might be involved in its surface expression.

Fas ligand

10.1002/sita.200400045

Cite

Citations (3)

Analysis of Cytotoxic Granules and Constitutively Produced Extracellular Vesicles from Large Granular Lymphocytic Leukemia Cell Lines

Cells (2024)

Lara Ploeger Patrick Kaleja Andreas Tholey Marcus Lettau Ottmar Janßen

Background: Large granular lymphocyte leukemias (LGLLs) are rare lymphoproliferative malignancies caused by clonal expansion of granular lymphocytes. T-cell LGLL and natural killer (NK) cell LGLL are defined based on their cellular origin. Their clinical manifestation and pathophysiology vary depending on the subtype and include, e.g., neutropenia, anemia, recurrent infections, and autoimmunity. A limited number of available patient-derived cell lines are considered valuable tools to study the biology of these malignancies. They differ in the expression of lineage-specific surface markers, but generally contain cytotoxic effector molecules in characteristic granules. Methods: We investigated the presence and release of lysosome-associated effector proteins in patient-derived LGLL cell lines by flow and imaging cytometry, by Western blotting and by bottom–up proteomics profiling. Results: The tested cell lines did not express FasL (CD178), but did express CD26/DPP4+. Intracellularly, we detected major differences in the abundance and subcellular distribution of granzymes, perforin, and granulysin. Similar differences were seen in enriched lysosome-related effector vesicles (LREVs). The proteomics profiling of enriched EVs from an NK-LGLL line (NKL) and a T-LGLL line (MOTN-1), confirmed individual profiles of effector molecules. Conclusion: Our analyses underscore the individual distribution of effector proteins but also open new routes to define the role of intra- and extracellular granules in the disease manifestation or pathology of LGLLs.

Granzyme

Granulysin

10.3390/cells13161310

Cite

Citations (1)

The PCH family member CIP4 is released from T cells upon activation-induced cell death

Cell Communication and Signaling (2009)

Marcus Lettau Andreas Beyer Ottmar Janßen

The 'Pombe Cdc15 homology' (PCH) family of adaptor proteins gained much attention only very recently. PCH proteins link membrane trafficking events to the actin cytoskeleton. Structurally, a so-called F-BAR domain characterizes all members of the PCH family and recent studies indicate that this domain enables PCH proteins to bind to and deform cellular membranes resulting in membrane curvature and tubulation. Accordingly, PCH proteins have been functionally associated with endo-/exocytosis and the trafficking of vesicles. As several PCH proteins interact with the death factor FasL, we were interested in the expression and function of PCH proteins in T cells in this context. Employing a new monoclonal anti-CIP4 antibody generated in our laboratory, we initially observed that the PCH family member CIP4 is expressed in T cells only after activation indicating a specific role in T cell maturation or effector function. Surprisingly, staining activated T cells for CIP4 followed by laser scanning microscopical inspection revealed that CIP4 seems to be somehow released from the cells in vesicular structures resembling exo- or ectosomes. The vesicle release can be visualized as a direct plasma membrane budding. Morever, CIP4-microvesicle formation and release proved to be enhanced during the initial phase of activation-induced T cell death triggered e.g. by exposure to staphylococcal superantigen. To us this indicates that this process might be relevant during T cell death to provide additional danger signals to neighboring cells. We are currently analysing the molecular content of these vesicles, the role of CIP4 in their generation and their impact on T cell biology.

Family member

10.1186/1478-811x-7-s1-a81

Cite

Citations (0)

Bispecific antibodies in acute lymphoblastic leukemia therapy

Expert Review of Hematology (2020)

Guranda Chitadze Anna Laqua Marcus Lettau Claudia D. Baldus Monika Brüggemann

Blinatumomab, first in a class of bispecific T-cell engagers, revolutionized treatment paradigm of B-cell precursor relapsed/refractory or minimal residual disease positive acute lymphoblastic leukemia (ALL) in adults and children, inducing deep remissions in a proportion of patients. However, significant numbers of patients do not respond or eventually relapse. Strategies for improvement of treatment outcomes are required.This review discusses the main structural and functional features of blinatumomab, and its place in the treatment of ALL. Furthermore, prospects to increase the efficacy of blinatumomab are addressed. The developments in the field of bispecific antibodies and their possible implications for treatment of ALL are reviewed.Better understanding the mechanisms of response and resistance to blinatumomab might help us to identify the group of patients benefiting most from treatment and to spare potentially toxic subsequent treatment strategies. Data emerging from ongoing clinical trials might change the treatment landscape of ALL and beyond. Early use of blinatumomab in frontline protocols with more advantageous treatment sequences and in combination with other targeted therapies might reduce the failure rates. Exponentially increasing number of novel treatment options and their possible combinations might complicate treatment decision-making without data from randomized trials.

Blinatumomab

Minimal Residual Disease

Refractory (planetary science)

10.1080/17474086.2020.1831380

Cite

Citations (5)

Novel monoclonal antibodies for the investigation of PCH family proteins

Signal Transduction (2007)

Marcus Lettau Alyn Beyer Ottmar Janßen

Abstract The pombe Cdc15 homology (PCH) protein family (also termed FCH/SH3 family) comprises 5 subgroups of structurally related polypeptides. The protein kinase C and casein kinase substrate in neurons 1 (PACSIN1), the CD2‐binding protein 1 (CD2BP1) and the Cdc42‐interacting protein 4 (CIP4) represent members of three individual subgroups. PCH proteins in general are supposed to link cytoskeletal elements to membrane trafficking machineries. In various cellular systems, PCH proteins are involved in lysosomal targeting, vesicular transport, and endocytotic as well as exocytotic processes. However, the specific molecular networks around individual PCH proteins and their localization in different cell populations need to be identified. We have recently reported that several members of the PCH family interact with the death factor FasL (CD178). This interaction is mediated via the SH3 domains of PCH proteins binding to the proline‐rich cytoplasmatic region of FasL. To analyze the role of endogenous PCH proteins in the context of FasL or other interactors, novel molecular tools are needed. We developed a set of monoclonal antibodies against three individual PCH family members. These novel reagents will help to analyze the presence and function of endogenous PCH proteins in lymphocytes and other cell types.

Homology

10.1002/sita.200600130

Cite

Citations (3)

Chitosan nanoparticles as antigen vehicles to induce effective tumor specific T cell responses

PLoS ONE (2020)

Frederik Walter Elsa Winter Sascha Rahn Judith Heidland Saskia Meier

Cancer vaccinations sensitize the immune system to recognize tumor-specific antigens de novo or boosting preexisting immune responses. Dendritic cells (DCs) are regarded as the most potent antigen presenting cells (APCs) for induction of (cancer) antigen-specific CD8+ T cell responses. Chitosan nanoparticles (CNPs) used as delivery vehicle have been shown to improve anti-tumor responses. This study aimed at exploring the potential of CNPs as antigen delivery system by assessing activation and expansion of antigen-specific CD8+ T cells by DCs and subsequent T cell-mediated lysis of pancreatic ductal adenocarcinoma (PDAC) cells. As model antigen the ovalbumin-derived peptide SIINFEKL was chosen. Using imaging cytometry, intracellular uptake of FITC-labelled CNPs of three different sizes and qualities (90/10, 90/20 and 90/50) was demonstrated in DCs and in pro- and anti-inflammatory macrophages to different extents. While larger particles (90/50) impaired survival of all APCs, small CNPs (90/10) were not toxic for DCs. Internalization of SIINFEKL-loaded but not empty 90/10-CNPs promoted a pro-inflammatory phenotype of DCs indicated by elevated expression of pro-inflammatory cytokines. Treatment of murine DC2.4 cells with SIINFEKL-loaded 90/10-CNPs led to a marked MHC-related presentation of SIINFEKL and enabled DC2.4 cells to potently activate SIINFEKL-specific CD8+ OT-1 T cells finally leading to effective lysis of the PDAC cell line Panc-OVA. Overall, our study supports the suitability of CNPs as antigen vehicle to induce potent anti-tumor immune responses by activation and expansion of tumor antigen-specific CD8+ T cells.

Cross-Presentation

10.1371/journal.pone.0239369

Cite

Citations (20)

Degranulation of human cytotoxic lymphocytes is a major source of proteolytically active soluble CD26/DPP4

Cellular and Molecular Life Sciences (2019)

Marcus Lettau Michelle Dietz Sarah Vollmers Fred Armbrust Christian Peters

Granzyme

Dipeptidyl peptidase

Tryptase

10.1007/s00018-019-03207-0

Cite