Krystian Fita

Universität Hamburg

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Katrin Lamszus

University Medical Center Hamburg-Eppendorf

Manfred Westphal

University Medical Center Hamburg-Eppendorf

Cécile L. Maire

Universität Hamburg

Malte Mohme

Universität Hamburg

Lasse Dührsen

University Medical Center Hamburg-Eppendorf

Ulf Geumann

Apceth Biopharma (Germany)

Felix G. Hermann

Goethe University Frankfurt

Simon Schliffke

University Medical Center Hamburg-Eppendorf

Mascha Binder

University Hospital of Basel

Nils Ole Schmidt

University Hospital Regensburg

Cooperative Institutions

Universität Hamburg

University Medical Center Hamburg-Eppendorf

University Cancer Center Hamburg

Eppendorf (Germany)

University of Lübeck

German Cancer Research Center

University of Tübingen

Heidelberg University

Martini-Klinik

Universidade de Santiago de Compostela

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Glioma escape signature and clonal development under immune pressure

Journal of Clinical Investigation (2020)

Cécile L. Maire Malte Mohme Michael Bockmayr Krystian Fita Kristoffer Riecken

Immunotherapeutic strategies are increasingly important in neuro-oncology, and the elucidation of escape mechanisms that lead to treatment resistance is crucial. We investigated the impact of immune pressure on the clonal dynamics and immune escape signature by comparing glioma growth in immunocompetent versus immunodeficient mice. Glioma-bearing WT and Pd-1-/- mice survived significantly longer than immunodeficient Pfp-/- Rag2-/- mice. While tumors in Pfp-/- Rag2-/- mice were highly polyclonal, immunoedited tumors in WT and Pd-1-/- mice displayed reduced clonality with emergence of immune escape clones. Tumor cells in WT mice were distinguished by an IFN-γ-mediated response signature with upregulation of genes involved in immunosuppression. Tumor-infiltrating stromal cells, which include macrophages/microglia, contributed even more strongly to the immunosuppressive signature than the actual tumor cells. The identified murine immune escape signature was reflected in human patients and correlated with poor survival. In conclusion, immune pressure profoundly shapes the clonal composition and gene regulation in malignant gliomas.

Signature (topology)

10.1172/jci138760

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Citations (35)

Figure S3 from Local Intracerebral Immunomodulation Using Interleukin-Expressing Mesenchymal Stem Cells in Glioblastoma

Malte Mohme Cécile L. Maire Ulf Geumann Simon Schliffke Lasse Dührsen

Suppl. Fig. 3. Flow cytometry analysis of T-cell surface marker expression

10.1158/1078-0432.22474902

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Diagnostic potential of extracellular vesicles in meningioma patients

Neuro-Oncology (2022)

Franz Ricklefs Cécile L. Maire Kathrin Wollmann Lasse Dührsen Krystian Fita

Extracellular vesicles (EVs) play an important role in cell-cell communication, and tumor-derived EVs circulating in patient blood can serve as biomarkers. Here, we investigated the potential role of plasma EVs in meningioma patients for tumor detection and determined whether EVs secreted by meningioma cells reflect epigenetic, genomic, and proteomic alterations of original tumors.EV concentrations were quantified in patient plasma (n = 46). Short-term meningioma cultures were established (n = 26) and secreted EVs were isolated. Methylation and copy number profiling was performed using 850k arrays, and mutations were identified by targeted gene panel sequencing. Differential quantitative mass spectrometry was employed for proteomic analysis.Levels of circulating EVs were elevated in meningioma patients compared to healthy individuals, and the plasma EV concentration correlated with malignancy grade and extent of peritumoral edema. Postoperatively, EV counts dropped to normal levels, and the magnitude of the postoperative decrease was associated with extent of tumor resection. Methylation profiling of EV-DNA allowed correct tumor classification as meningioma in all investigated cases, and accurate methylation subclass assignment in almost all cases. Copy number variations present in tumors, as well as tumor-specific mutations were faithfully reflected in meningioma EV-DNA. Proteomic EV profiling did not permit original tumor identification but revealed tumor-associated proteins that could potentially be utilized to enrich meningioma EVs from biofluids.Elevated EV levels in meningioma patient plasma could aid in tumor diagnosis and assessment of treatment response. Meningioma EV-DNA mirrors genetic and epigenetic tumor alterations and facilitates molecular tumor classification.

Extracellular Vesicles

10.1093/neuonc/noac127

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Sex-biased immune response in glioblastoma patients

Brain and Spine (2024)

Alice Ryba Cécile L. Maire Alessandra Rünger Krystian Fita Manfred Westphal

10.1016/j.bas.2024.103706

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Figure S5 from Local Intracerebral Immunomodulation Using Interleukin-Expressing Mesenchymal Stem Cells in Glioblastoma

Malte Mohme Cécile L. Maire Ulf Geumann Simon Schliffke Lasse Dührsen

Suppl. Fig. 5. Spleen weight

10.1158/1078-0432.22474896.v1

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Data from Local Intracerebral Immunomodulation Using Interleukin-Expressing Mesenchymal Stem Cells in Glioblastoma

Malte Mohme Cécile L. Maire Ulf Geumann Simon Schliffke Lasse Dührsen

<div>AbstractPurpose:Mesenchymal stem cells (MSCs) show an inherent brain tumor tropism that can be exploited for targeted delivery of therapeutic genes to invasive glioma. We assessed whether a motile MSC-based local immunomodulation is able to overcome the immunosuppressive glioblastoma microenvironment and to induce an antitumor immune response.Experimental Design:We genetically modified MSCs to coexpress high levels of IL12 and IL7 (MSCIL7/12, Apceth-301). Therapeutic efficacy was assessed in two immunocompetent orthotopic C57BL/6 glioma models using GL261 and CT2A. Immunomodulatory effects were assessed by multicolor flow cytometry to profile immune activation and exhaustion of tumor-infiltrating immune cells. Diversity of the tumor-specific immune response as analyzed using T-cell receptor sequencing.Results:Intratumoral administration of MSCIL7/12 induced significant tumor growth inhibition and remission of established intracranial tumors, as demonstrated by MR imaging. Notably, up to 50% of treated mice survived long-term. Rechallenging of survivors confirmed long-lasting tumor immunity. Local treatment with MSCIL7/12 was well tolerated and led to a significant inversion of the CD4+/CD8+ T-cell ratio with an intricate, predominantly CD8+ effector T-cell–mediated antitumor response. T-cell receptor sequencing demonstrated an increased diversity of TILs in MSCIL7/12-treated mice, indicating a broader tumor-specific immune response with subsequent oligoclonal specification during generation of long-term immunity.Conclusions:Local MSC-based immunomodulation is able to efficiently alter the immunosuppressive microenvironment in glioblastoma. The long-lasting therapeutic effects warrant a rapid clinical translation of this concept and have led to planning of a phase I/II study of apceth-301 in recurrent glioblastoma.</div>

10.1158/1078-0432.c.6528933.v1

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10.1063/1.4921591.6

Default Digital Object Group (2015)

b R. Schönherr b M. Klinge J. M. Rudolph Krystian Fita D. Rehders

X-ray crystallography requires sufficiently large crystals to obtain structural insights at atomic resolution, routinely obtained in vitro by time-consuming screening. Recently, successful data collection was reported from protein microcrystals grown within living cells using highly brilliant free-electron laser and third-generation synchrotron radiation. Here, we analyzed in vivo crystal growth of firefly luciferase and Green Fluorescent Protein-tagged reovirus μNS by live-cell imaging, showing that dimensions of living cells did not limit crystal size. The crystallization process is highly dynamic and occurs in different cellular compartments. In vivo protein crystallization offers exciting new possibilities for proteins that do not form crystals in vitro.

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10.1063/1.4921591.6

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Genome-wide DNA methylation profiles distinguish silent from non-silent ACTH adenomas

Acta Neuropathologica (2020)

Franz Ricklefs Krystian Fita Roman Rotermund András Piffkó Simone Schmid

10.1007/s00401-020-02149-3

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Citations (15)