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IRTG: Integrated Research Training Group SFB 685  / Associated Members

Associated Member: Nicole Armbruster

Name:

Nicole Armbruster

Project:

A03

Supervisor:

Stella Autenrieth

Email

Opens window for sending emailnicole.armbruster(@)uni-tuebingen.de

Status:

PhD student

Associated:

15.10.2013 -

Abstract:

Staphylococcus aureus  is a highly successful human pathogen whose virulence depends largely on sophisticated strategies to evade and exploit innate and adaptive immune responses. Virulence of emerging community-associated methicillin-resistant S. aureus (CA-MRSA) relies on phenol-soluble modulin (PSM) peptide toxins. In recent studies it was shown that CA-MRSA use PSMs to attract and stimulate neutrophils via the formyl peptide receptor 2 (FPR2), a G-protein coupled receptor, and to disrupt neutrophils when sufficiently high PSM concentrations are reached. Furthermore, PSMs appear to interfere with adaptive immunity by counteracting the stimulation of DCs by TLR ligands thereby diminishing DC maturation, proinflammatory cytokine secretion, and antigen uptake, leading to reduced Th1 but more pronounced regulatory T-cell response in vitro. Our aim is to investigate the molecular mechanisms underlying the induction of the regulatory T-cell response by PSM-treated DCs and the relevance of PSM-modulated DCs in vivo.


Associated Member: Katharina Böhm

Name:

Katharina Sonja Böhm

Project:

C01

Supervisor:

Martin Röcken

Email:

Opens window for sending emailKatharina.Boehm(@)med.uni-tuebingen.de

Status:

PhD-student

Associated:

01.11.2014 -

Abstract:

Cellular senescence plays an important role in tissue development, homeostasis and cancer control1-3. It was known as an intrinsic growth control mechanism that prevents the transformation of pre-malignant lesions into overt malignancy. 

We recently found that, in addition, exogenous signals delivered by the immune system can arrest development and growth of cancers through the induction of cellular senescence1. Most importantly, cytokine induced senescence can even arrest established cancers in humans (manuscript in preparation). Thus, in addition to the cancer control by induction of cell death, the immune system can arrest ß-cancer cells and a large number of cancer cell lines by driving them into senescence via the activation of the p16INK4a/Rb pathway in absence of apoptosis1. 

Previous studies demonstrate that senescent cells are frequently removed from the tissues during embryogenesis. Similarly, we and others found that senescent pre-malignant cancer cells and senescent melanoma cells (manuscript in preparation) are frequently cleared without major signs of inflammation 2,3. Yet, the mechanism underlying the clearing of the senescent cancer cells remains to be elucidated. Here, we will therefore address the mechanisms that clear senescent cancer cells in vitro and in vivo. We will especially focus on three major aspects: 1) We will first ask whether macrophages and dendritic cells can phagocytose senescent cancer cells; subsequently we will compare the phagocytosis of senescent cells with that of necrotic or apoptotic cells. 2) We will investigate eat me and find me signals, and chemoattractants that render cancer cells recognizable to the immune system. 3) We will investigate how the immune system ultimately clears senescent cancer cells, in vitro and in vivo; we are especially intrigued by the question of whether phagocytosis would be the major mode of cancer cell clearance or whether other mechanisms are involved in the clearance of the large number of senescent cancer cells in vivo.

Understanding the process of cancer immune surveillance by senescence induction may unravel cytokine-induced cellular senescence as a key mechanism involved in efficient cancer immune therapy.

 

1 Braumüller, H., Wieder, T., Brenner, E., Aszmann, S., Hahn, M., Alkhaled, M., Schilbach, K., Essmann, F., Kneilling, M., Griessinger, C., et al. (2013). T-helper-1-cell cytokines drive cancer into senescence. Nature 494, 361-365.

2 Muñoz-Espín, D., Cañamero, M., Maraver, A., Gómez-López, G., Contreras, J., Murillo-Cuesta, S., Rodríguez-Baeza, A., Varela-Nieto, I., Ruberte, J., Collado, M., et al. (2013). Programmed Cell Senescence during Mammalian Embryonic Development. Cell 155, 1104-1118.

3 Kang, T.-W., Yevsa, T., Woller, N., Hoenicke, L., Wuestefeld, T., Dauch, D., Hohmeyer, A., Gereke, M., Rudalska, R., Potapova, A., et al. (2011). Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547-551.


Associated Member: Michael Ghosh (PhD)

Name:

Michael Ghosh

Project:

C05

Supervisor:

Stefan Stevanovic

Email:

Opens window for sending emailMichael.ghosh(@)uni-tuebingen.de

Status:

PhD-student

Associated:

01.10.2016 -

Abstract:

Analysis of differential antigen processing in cancers and prevalence of presentation of tumor exclusive antigens by targeted mass spectrometry

Immunotherapy has led to a revolution in cancer therapy. Current hopes are that antigen specific immunotherapies such as genetically modified T-cells or soluble HLA:peptide engaging constructs may further advance this successful development. Understanding which targets are essentially presented by cancer cells and cannot be found on any benign tissue is of utmost importance for this development.
Large scale HLA ligandome analyses via data dependent LC-MS/MS has enabled us to characterize the immunopeptidomic landscapes of various malignant and benign tissues and allowed us to identify many tumor-specific HLA ligands. A major pitfall of this discovery-oriented approach is that because of its heuristic nature and low sensitivity the actual presentation frequency of HLA ligands is elusive and likely underestimated. By employing a highly sensitive targeted mass spectrometry approach we want in our first aim determine the exact prevalence of presentation of tumor exclusive HLA ligands in different cancers and metastases. Second, we want to use this approach to validate specific examples of differential antigen processing in cancers which are evident from our large in-house ligandome database. Our third aim is to implement data independent acquisition, a novel mass spectrometry technique aimed at the identification of all peptides within a given sample for HLA ligandome analysis.


PhD scholarship holder: Yamel Irais Cardona Gloria

Name:

Yamel Irais Cardona Gloria

Project:

A15

Supervisor:

Alexander Weber

Email

Opens window for sending emailyamel.cardona(@)student.uni-tuebingen.de

Scholarship:

01.11.2014 - 30.10.2015

Associated:

01.11.2015 -

Abstract:

Oncogenic mutation in MyD88  

B-cell malignancies, such as chronic lymphocytic leukemia, mucosa-associated lymphoid tissue lymphoma and diffuse large B-cell lymphoma, are diseases with considerable mortality and morbidity around the world. Whole-genome sequencing correlated (5-90%) these B-cell malignancies and others, with a heterozygous mutation (Leu 265 Pro) in the MyD88 gene. MyD88 is a pivotal adaptor protein of Toll-like receptor (TLR) and Interleukin-1 receptor signaling pathways, which are important drivers of innate immunity. Furthermore, MyD88 has being recently related to B-cell receptor and Phosphoinositide-3-kinase pathways, which take part in important regulatory circuits in B-cells. Previous data suggests L265P mutation in MyD88 to be an early driver of the B-cell type malignancies, because of its hyperactive phenotype. Moreover, preliminary data demonstrated that L265P MyD88 has an altered post-translational modification; it sequesters the wildtype version and raises a L265P-specific epigenetic signature. Thus, we hypothesize that the sequestering of the functional version impairs Mal-dependent TLR signaling, but promotes its interaction with endosomal TLRs or/and members of the non-canonical BCR and PI3K pathways. And these intracellular disruptions could be related to the altered post-translational modification of MyD88 and the probably consequent epigenetic signature. To address this, we aim to stablish the L265P mutation in MyD88 in a B-cell specific murine model and asses L265P effects on MyD88 in terms of post-translational modification, interactions, signaling and epigenetics.


Associated Member: Jana Hau (MD)

Name:

Jana Hau

Project:

C03

Supervisor:

Peter Lang / Patrick Schlegel

Email

Opens window for sending emailJana.Hau(@)gmx.de

Associated:

20.04.2016 -

Abstract: 

Preclinical evaluation of a novel adapter CAR system

Adoptive transfer of T-cells genetically engineered to express chimeric antigen receptors (CAR) has demonstrated remarkable therapeutic potential in various clinical trials. CAR-T-cell (CAR-T) therapy against the B-cell antigen CD19 resulted in complete remission in > 80% of patients suffering from refractory end-stage CD19-positive leukemia. In contrast, clinical studies have also demonstrated major limitations of this approach.

In order to address these limitations, we have created an adapter-CAR (aCAR) approach. The idea of the aCAR system is to split antigen recognition and T-cell activation by creating a CAR-construct that does not bind to an antigen present on a target cell, but to a special tag, conjugated to an adapter molecule, e.g. a mAb, which facilitates antigen specify.

As part of the present medical doctoral thesis, we have created 10 different aCAR constructs all containing a scFv against a specific tag conjugation, 41-BB co-stimulation and CD3-zeta, but differing in scFv configuration, spacer length and property in order to find out if there is a T-cell activation and lysis in vitro against target cells expressing different antigens.

 

 

Associated Member: Florian Heubach (PhD)

Name:

Florian Heubach

Project:

C03

Supervisor:

Peter Lang

Email:

florian.heubach@med.uni-tuebingen.de

Status:

PhD-student

Associated:

01.04.2016 -

Abstract:

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Associated Member (PhD): Anna Keib

Name:

Anna Keib

Project:

Graduiertenakademie

Supervisor:

Kevin Dennehy 

Email:

Opens window for sending emailmailto:Anna.Keib(@)med.uni-tuebingen.de

Status:

PhD-student

Associated:

01.04.2016 -

Abstract:

Validation of optimal targets for adoptive T-cell therapy of adenovirus infection

Adenovirus infection is the major cause of infectious mortality in children following haematopoietic stem cell transfer. Antigen-specific adoptive T-cell therapy is a powerful approach to treat viral infections in immunocompromised patients, but remains to be established as a broadly applicable therapy (Günther et al., 2015 J Immunotherapy 38: 267). The aim of this project is to expand the number of target epitopes that can be used in adoptive transfer therapy.


MD scholarship holder: Ronald Keller (MD)

Name:

Ronald Keller (MD)

Project:

B07

Supervisor:

Klaus Schulze-Osthoff

Email

Opens window for sending emailronald.keller(@)student.uni-tuebingen.de

Scholarship:

01.01.2016 - 30.06.2016

Associated:

01.07.2016 -

Abstract:

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Associated Member: Giray Korkmaz

Name:

Giray Korkmaz

Project:

A13

Supervisor:

Julia-Stefanie Frick

Email:

Opens window for sending emailGiray.Korkmaz(@)med.uni-tuebingen.de

Status:

PhD-student

Associated:

01.09.2013 - 

Scholarship:

Abstract:

The interplay between the gut microbiota and gut immune system is crucial for the pathogenesis of the intestinal inflammatory diseases. Our group has previously shown that the structure of the lipopolysaccharide (LPS) of commensal bacteria has a strong influence on the maintenance of intestinal homeostasis. We identified Bacteroides vulgatus strain mpk LPS to prevent intestinal inflammation in IL2-/- mice whereas the E. coli strain mpk induced colitis in IL2-/- mice. Nevertheless, the outcome of bacterial stimulation depends on the intricate network of immunomodulation, with numerous factors such as recognition of bacteria by distinct receptors, their associated signaling pathways and the type of immune cells being at play. This considered, our research aims at investigating these multiple factors;

(i)  Definition of anti-inflammatory and pro-inflammatory LPS structures: LPS from pro-inflammatory E. coli mpk and anti-inflammatory B. vulgatus mpk will be isolated and their biological activity will be determined in vitro. Isolated LPS species will be used to stimulate wild type and TLR deficient mouse bone marrow isolated dendritic cells followed by analyzing cell surface marker expression profiles by FACS and cytokine secretion patterns by ELISA. 

(ii)   Role of dendritic cells in gut immune homeostasis: In this part of the study we aim to clarify whether dendritic cells are crucial for mediating the pro- and anti-inflammatory effects of the intestinal microbiota. To be able to study DC function in vivo we will employ Rag1-/- ∆DC mice. The dendritic cell deficient mice hosting specific pro-inflammatory and anti-inflammatory intestinal microflora will be transplanted with naïve CD4 T-cells, thereby modelling T cell transfer colitis in a DC deficient background. The disease occurrence and the course of disease are to be monitored by PET/MRT, and the activation and polarization of lamina propria/mesenteric lymph node T-cells will be investigated by analyzing cell surface markers and cytokine secretion profiles. 

(iii)   Definition of the pattern recognition receptor which mediates the LPS effect: In this project we aim to define the extent of the involvement of TLR2 and TLR4 in mediating the pro- or anti- inflammatory effects of different commensal LPS. To identify the PRR mediating the LPS effects we will use Rag1-/- mice with a deficient TLR2 or TLR4 signalling. Induction of colitis will be monitored and prevention of disease by feeding of protective bacteria or the respective LPS will be analyzed.

(iv)  Defining the differences in intracellular pathways downstream of LPS recognition: In this part of the study we aim to analyze the differences in cellular responses of dendritic cells when stimulated by LPS from E.coli and B. vulgatus. Our preliminary data shows that stimulation of mouse bone marrow derived dendritic cells with B. vulgatus results in a semi-mature state, whereas stimulation by E.coli results in a potent dendritic cell response and full maturation. We will perform a phosphoproteomic as well as total shotgun proteomic analyses to define the differences in intracellular responses leading to the semi-mature and mature phenotypes observed. 

Taken together our projects aim to provide more information on the biological activity of different LPS, and on the multifaceted responses of the gut immune network, hopefully leading to new preventive or even therapeutic strategies in intestinal inflammatory diseases.  


Associated Member: Felipe Jose Nobre Lelis

Name:

Felipe Jose Nobre Lelis 

Project:

A14

Supervisor:

Dominik Hartl

Status:

PhD-student

Associated:

01.09.2014

Email:

Opens window for sending emailfelipe.lelis(@)med.uni-tuebintgen.de

Abstract:

B cells are key components of the humoral adaptive immune response. Their main function is to produce antibodies, but they are also involved in several pathological conditions, such as infections, autoimmune and autoinflammatory diseases and others, . Myeloid-derived suppressor cells (MDSCs) are innate immune cells, known to suppress T-cells function in various conditions, such as cancer and infection. However, it is not yet known if MDSCs interact with B cells. By using in vitro and in vivo modelling systems, we are trying to dissect the effects of MDSCs on B-cell responses

 


Associated Member: Manuel Liaci

Name:

Manuel Liaci

Project:

B03

Supervisor:

Thilo Stehle

Email:

Opens window for sending emailantonio-manuel.liaci(@)uni-tuebingen.de

Status:

PhD-student

Associated:

01.04.2013 -

Abstract:

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Associated Member: Maren Lübke (PhD)

Name:

Maren Lübke

Project:

C05

Supervisor:

Stefan Stevanovic

Email:

Opens window for sending emailmaren.luebke(@)student.uni-tuebingen.de

Status:

PhD-student

Associated:

01.10.2015 -

Abstract:

xyz

 

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PhD scholarship holder: Jan März (PhD)

Name:

Jan März (PhD)

Project:

A13

Supervisor:

Julia-Stefanie Frick

Email

Opens window for sending emailJan.maerz(@)med.uni-tuebingen.de

Scholarship:

15.06.2015 - 14.06.2016

Associated:

15.06.2016 -

Abstract:

Outer membrane vesicles derived from B.vulgatus mpk as a novel acellular therapeutical agent for treatment of inflammatory disorders

Outer membrane vesicles (OMVs) are produced in many pathogenic and non-pathogenic bacteria by ubiquitous blebbing of the outer membrane. These vesicles consist of lipids, proteins, lipopolysaccharide and other luminal molecules. Supplementary to the roles in pathogenesis, cell-to-cell communication and stress response, recent work has suggested that OMVs play important roles in immunomodulation and the establishment of a balanced gut microbiota. This project focuses on the influences of B. vulgatus mpk derived OMVs on the innate immune system. It is already know that the symbiotic gram-negative B. vulgatus mpk has unique features concerning its impacts on inflammatory disorders of the gut homeostasis. This bacterium is able to protect from chronic colitis in T cell transplanted Rag1-/- mice. Additionally, it can also reduce inflammation in mice that are already suffering from colitis symptoms. Responsible for these anti-inflammatory effects of B. vulagtus mpk is the induction of semi-mature bone marrow derived dendritic cells (BMDCs) in the host. Successful isolation and purification of OMVs and stimulation of antigen presenting cells (DCs) leads to the same tolerant semi-mature phenotype that it is observed when the whole bacterium is used. Furthermore, experiments with wt, TLR2-/- BMDCs, TLR4-/- BMDCs and TLR2-/-x TLR4-/- BMDCs indicate the crucial role of different Pathogen-associated molecular patterns (PAMPs) of the bacterial membrane to maintain the intestinal homeostasis. In addition to bacterial LPS, binding to host TLR4, a yet unknown compound to host TLR2 is important for the conversion into a semi-maturation state. Due to the findings that B.vulgatus OMVs are internalized by BMDCs where they end in endosomal and lysosomal compartments of the host cell, not only compounds located in bacterial cell membranes might account for immunomodulating effects. We propose that outer membrane vesicles derived from non-pathogenic B. vulgatus mpk are promising acellular drugs for therapeutical treatment of disease like e.g. colitis, type-I-diabetes or multiple sclerosis. Therefore we want to identify the structures and components which are essential for the immunomodulatory effects of the OMVs. Thus, we want to create a hypervesiculating B. vulgatus mpk mutant strain to gain more insights how exactly those OMV components affect host target cells to finally design bioengineered bacterial outer membrane vesicles providing the maximum anti-inflammatory properties as a general tool for successful therapy of immunological disorders.


Associated Member: Timo Manz

Name:

Timo Manz

Project:

DKTK (German Cancer Consortium)

Supervisor:

Gundram Jung

Email:

Opens window for sending emailt.manz(@)dkfz-heidelberg.de

Status:

PhD-student

Associated:

01.05.2015 -

Abstract:

Development of checkpoint modulating antibodies for clinical use

The use of monoclonal antibodies (mAbs) in the treatment of a various number of cancer types was established as a successful therapeutic approach. Typical strategies target the tumor cells by the use of monoclonal antibodies such as Trastuzumab (Herceptin), Bevacizumab (Avastin) and Cetuximab (Erbitux). However, the general goal in the field of immunotherapy is recruiting potent immune cells such as NK-cells or T-lymphocytes to the tumor site and promoting immune responses specifically targeting the cancer cells. A broad range of agents has been tested as immune stimulating reagents including cancer vaccines, cytokine-based treatment, targeting of Toll-like receptors and mAbs targeting tumor surface antigens. Progress in the research of the immune system showed the important role of co-stimulatory and co-inhibitory receptors in the interplay of the immune system with cancer cells. Most prominent members of these receptors are CD28, Light, OX40 and 4-1BB.Thus, leading to the development of novel immunomodulating agents, which are enhancing an anti-tumor immune response. Further understanding in the mechanisms and resistance of cancer lead to the development of the first checkpoint inhibitors Pembrolizumab (Keytruda) which is targeting PD1 and Ipilimumab (Yervoy) targeting CTLA-4 having achieved remarkable clinical success.
With modern methods of protein-engineering our group aims to design novel immunomodulating antibody therapeutics targeting cancer cells. By combining co-stimulating agents and checkpoint inhibitors, we want to develop a defined therapeutic strategy to further increase the potential of checkpoint modulating antibodies and reduce possible side effects in the patient.


PhD scholarship holder: Stefanie Maurer (née Raab)

Name:

Stefanie Maurer (née Raab)

Project:

A07

Supervisor:

Helmut R. Salih

Email

st.raab(@)student.uni-tuebingen.de

Scholarship:

01.07.2012 - 30.06.2013

Associated:

01.07.2013 -

Abstract:

Natural killer (NK) cells are important players both in tumor immune surveillance and after hematopoietic stem cell transplantation (SCT) in the context of graft-vs.-host-disease (GvHD) and graft-vs.-leukemia (GvL) effects. Standard treatment for SCT patients includes inhibitors of calcineurin, a phosphatase which allows NFAT (nuclear factor of activated T cells) to translocate into the nucleus and regulate transcription. NFAT has been described in T cells but was meanwhile found in a variety of immune effector cells of the myeloid and lymphoid lineage. Surprisingly little is yet known regarding the role of NFAT in NK cells.
While abolished calcineurin activity does not influence NK cell development, it is crucial for their effector functions. Characterisation of the role of the different members of the NFAT family in NK cells, as envisaged in the granted project, is therefore not merely an intersting question in basic research but may also be valuable for improving treatment after SCT. 


Associated Member: Melanie Müller

Name:

Melanie Müller

Project:

from the Graduate Center of the Medical Faculty (School of Immunology)

Supervisor:

Ralf Amann

Email:

Opens window for sending emailmelan.mueller(@)student.uni-tuebingen.de

Status:

PhD-student

Associated:

01.10.2014 -

Abstract:

Viral vectors represent a promising platform for the development of recombinant vaccines to prevent infectious diseases. More recently, they were utilized for the development of new, innovative concepts, e.g. the development of therapeutic cancer vaccines.  

The Orf virus (ORFV) belongs to the family of poxviridae and has several attributes making it a perfect candidate for virus-based vaccines. During the last decade, the excellent immune stimulating and prophylactic capacity of ORFV-based recombinants against numerous different viral diseases have been demonstrated manifold. Nevertheless, the mechanism of immune stimulation/induction remaines poorly understood and needs further investigation. 

With the aid of a recombinant ORFV, expressing a fluorescent marker, the mode of action and the immune cells involved in this immune activation will be investigated. The capability to cause T-cell priming, as an integral part of the immune activation, will be studied in more detail using the model antigens Melan A and pp65 (hCMV). Further optimization of the immune stimulatory capability of ORFV shall be achieved by coexpression of adequate cytokines together with the target protein insert.


MD scholarship holder: Tobias Münzner (MD)

Name:

Tobias Münzner (MD)

Project:

A13

Supervisor:

Julia-Stefanie Frick

Email

Opens window for sending emailtobias.muenzner(@)student.uni-tuebingen.de

Scholarship:

01.11.2015 - 30.04.2016

Associated:

01.05.2016 -

Abstract:

Cystatin C mediated regulation of Proteinkinase C delta activity – a novel mechanism for maintaining intestinal homeostasis?

The intestinal human immune system has to accomplish different challenges. Besides antagonizing pathogens in the gut, it has to tolerate commensals or probiotics the human organism can benefit from. This tolerance of commensal bacteria in the absence of pathogens can be severely disturbed under certain conditions, thus leading to pathological inflammatory disorders of the gut, i.e. inflammatory bowel disease such as colitis.

Different commensals affect host immune responses in the intestine in distinct ways. We could already demonstrate that, Bacteroides vulgatus mpk provides anti-inflammatory properties, whereas another apathogenic gut commensal E. coli mpk obtains pro-inflammatory properties. B. vulgatus was even able to protect from E. coli mpk mediated experimental colitis in mice. This was associated with the induction of a tolerogenic dendritic cell phenotype. Tolerogenic DCs are unable to activate CD4+ T cells and are non-responsive to further bacterial stimuli.

Moreover, based on our characterization of tolerogenic DCs, we suppose that the tolerance-inducing properties of B. vulgatus are mediated by the binding of its unique lipopolysaccharide to toll-like receptor 4(TLR4). We could already show that the protein Cystatin C plays a key role within the signaling pathway downstream of TLR4, as it directly interacts with members of the 14-3-3 protein family. A certain member of the 14-3-3- family, namely the protein 14-3-3ζ, was shown to activate the enzymatic activity of Proteinkinase Cδ(PKCδ), a kinase involved in inflammatory processes. 

Therefore we want to elucidate if B. vulgatus mediated induction of tolerogenic DCs results in downregulation of PKCδ, and if yes, if this is mediated by a TLR4 signaling induced alteration in the binding behavior of Cys C to 14-3-3ζ. In that case this would be a novel regulatory signaling pathway for PKCδ activity regulation. Additionally, we want to clarify if PKCδ and 14-3-3ζ would be an appropriate drug target for the treatment of inflammatory bowel disease.


PhD scholarship holder: Hasan-Halit Öz
Associated Member: Hasan-Halit Öz

Name:

Hasan-Halit Öz

Project:

A14

Supervisor:

Dominik Hartl

Email

Opens window for sending emailhasan-halit.oez(@)student.uni-tuebingen.de

Scholarship:

01.10.2013 - 30.09.2014

Associated:

01.10.2014 -

Abstract:

Homeostasis and functionality of myeloid-derived suppressor cell subtypes in vivo

Myeloid-derived suppressor cells (MDSCs) are an innate immune cell population, which regulate effector T cell responses. Initially investigated in cancer, their role has broadened to a central role of these „innate Tregs“ in inflammatory and infectious disease conditions. Recent studies suggest that different subtypes of MDSCs exist, with neutrophilic (PMN-MDSC) and monocytic (M-MDSC) as the most prominent ones. However, the dynamics, kinetics and functional characteristics of MDSC subtypes are poorly understood. We defined in previous studies pathways that regulate MDSC generation in vitro, namely (i) Pseudomonas aeruginosa infection, (ii) Asthmatic inflammation and (iii) Chitin-bearing CARD9-dependent fungi. The in vivo relevance and functional contribution of distinct MDSC subtypes to these disease conditions remain to be defined, which is the key objective of this PhD thesis.


Associated Member: Kevin Röhle

Name:

Kevin Röhle

Project:

C05/C14

Supervisor:

Stefan Stevanović

Email

Opens window for sending emailkevin.roehle(@)student.uni-tuebingen.de

Associated:

15.10.2014 - 

Abstract

Characterization and specificity analysis of tumor infiltrating lymphocytes in ovarian carcinoma

Ovarian cancer (OvCa) is the most lethal gynecological cancer in women with an overall poor prognosis due to late diagnosis and frequent resistance to chemotherapy. OvCa is also highly immunogenic characterized by a generally strong infiltration with lymphocytes.

The amount and cellular composition of the infiltrating lymphocytes even presents an independent prognostic factor in OvCa patients. Based on previous work in the department of immunology several tumor associated HLA ligands from established OvCa antigens (CA-125, Mucin 1, Mesothelin) have been identified to be naturally presented by OvCa cells. If and to which extent these HLA ligands are recognized by TILs and whether specific T cells are able to elicit an anti-tumor response is however still unknown. 

The goal of my PhD will therefore be to analyze the specificity and functionality of tumor infiltrating lymphocytes and compare them to peripheral blood T cells of ovarian cancer patients. 

TILs will be isolated from fresh tumor tissue of patients undergoing surgery. At the same time immunopeptidome analysis will be performed starting from the same patient’s tumor material to identify tumor associated HLA ligands which are likely to be recognized by infiltrating lymphocytes. Broadly recognized virus derived epitopes from EBV, CMV or Influenza will be employed as positive controls to determine the general functionality of infiltrating T cells. T-cell reactivity and specificity will be assessed by IFN-γ ELISPOT as well as intracellular cytokine and multimer screening. 


Associated Member: Kathrin Rothfelder

Name:

Kathrin Rothfelder

Project:

A07

Supervisor:

Helmut R. Salih

Email

Opens window for sending emailkathrin.rothfelder(@)med.uni-tuebingen.de

Status:

PhD-Student

Associated:

01.10.2013 -

Abstract:

Over the years several studies have suggested that cancers might be hierarchically organized with only a small fraction of cells having the ability to self re-new, give rise to differentiated cells and maintain disease. These cells have been termed Cancer Stem Cells (CSCs) and have been described in detail in Acute Myeloid Leukemia (AML), as well as several solid tumors.  In AML CSCs have been suggested to reside in the immature CD34+CD38- population, which gives rise to more mature CD34- progenitor cells. Recent data however have challenged this paradigm demonstrating that CSC activity may also reside in the CD34- subpopulation for which no CSC marker exists to date. The absence of a clear CSC marker applies for acute lymphoblastic leukemia (ALL) as well. Consequently, the development of methods for the identification of these CSC is of special interest. For my PhD project I focus on the characterization of the particular “immunological phenotype” of CSC in acute leukemias by flow cytometry, FACS, qPCR, in vitro colony forming assays and xenotransplantation of cancer cells into immune deficient mouse models. Moreover, we will study the interaction of NK cells, cytotoxic lymphocytes of the innate immune system, with CSC. It is believed that CSC are resistant to conventional cancer treatments due to special molecular features and thus play a major role in leukemia relapse. However it is unknown to which extent the ability of CSC to evade the immune surveillance is involved in this process. As NK cells have been shown to play an important role in leukemia immunosurveillance, we want to test NK cell reactivity against CSC via cytotoxicity assays, ELISA as well as degranulation assays.


Associated Member: Ferdinand Salomon

Name:

Ferdinand Salomon

Project:

from the Graduate Center of the Medical Faculty (School of Immunology)

Supervisor:

Ralf Amann

Email

Opens window for sending emailferdinand.salomon(@)student.uni-tuebingen.de

Status:

PhD-student

Associated:

01.07.2015 -

Abstract:

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PhD scholarship holder: Tharmila Sanmuganantham
Associated Member: Tharmila Sanmuganantham

Name:

Tharmila Sanmuganantham

Project:

A15

Supervisor:

Alexander Weber

Email

Opens window for sending emailtharmilas(@)yahoo.com

Scholarship:

01.03.2014 - 28.02.2015

Associated:

01.03.2015 -

Abstract:

Influence of TLR and NLR genetic variants on commensal bacterial detection, gut immunity and microbiome diversity in humans

 

In the innate immune system the first detection of microbe-associated molecular patterns (MAMPs) requires germ-line encoded pathogen recognition receptors (PRRs), such as Toll-like receptor (TLR) and Nod-like receptor (NLR). In murine models, current data for TLR5, a receptor for bacterial flagellin, suggest that TLR5-mediated immunity modulates the intestinal microbiome in the gut of mammals. Recent studies, again mainly from murine models, moreover have implicated TLRs and NLRs in gut-related diseases, e.g. colorectal cancer or metabolic diseases. 

Recently, in our lab, several TLR5 Single Nucleotide Polymorphisms (SNPs) were identified as significantly associated with human colorectal cancer (CRC) survival and functional studies point to a putative functional link between the microbiome, TLR5 signalling and CRC. We suggest that TLRs and NLRs may act in concert for a finely-tuned equilibrium between the host`s innate immune system and the microbiome, which may be perturbed by hypo- or hyper-functional alleles of TLRs or NLRs. By studying functionally relevant TLR and NLR SNPs in healthy donors, in terms of their immune activation and microbiome influence, we aim to further define their contribution to gut immunity and colorectal cancer


Associated Member: Janinie Schmidt

Name:

Janinie Schmidt

Project:

B08

Supervisor:

Falko Fend / Leticia Quantanilla-Martinez de Fend

Email:

Janine.Schmidt(@)med.uni-tuebingen.de

Status:

PhD-student

Associated:

01.08.2012 -

Abstract:

Identification of secondary genetic alterations of premalignant stages needed for progression to manifest follicular lymphoma

Follicular lymphoma (FL) is one of the most common malignant lymphomas in adults. The genetic hallmark of this disease is the chromosomal translocation t(14;18)/IGH-BCL2 leading to overexpression of the BCL2 protein, which results in a slow expansion of long-lived B-lymphocytes resistant against programmed cell death. Recently, microscopic infiltrates of BCL2-positive cells carrying the hallmark genetic marker of FL have been identified in reactive lymph nodes of healthy individuals and denominated FL “in situ” (FLIS). FLIS probably represents the earliest phenotypically detectable step in follicular lymphomagenesis. However, the genetic events responsible for evolution of this preneoplastic lesion into overt FL are largely unknown. The goal of our project is to identify genetic alterations needed for transformation of FLIS to manifest FL. To this end, whole genome and whole exome next generation sequencing will be performed on a small number of FL cases. Alterations identified in this screen will be targeted by Array comparative genomic hybridization and next generation sequencing performed on FLIS and paired FLIS/FL samples. Our project shall provide better understanding of early FL pathogenesis through describing key molecular events driving premalignant t(14;18)+ cells into clinical lymphoma.


PhD scholarship holder: Bastian Schmied

Name:

Bastian Schmied

Project:

A07

Supervisor:

Helmut Salih

Email

Opens window for sending emailbschmied88(@)googlemail.com

Scholarship:

01.01.2015 - 31.12.2015

Associated:

01.11.2016 -

Abstract:

Bispecific immunoreceptor fusion proteins for induction of anti-leukemia immunity

Monoclonal antitumor-antibodies (mAb) like Rituximab mediate their effects, at least in great part, by induction of „antibody-dependent cellular cytotoxicity“ (ADCC) via activation of the Fc receptor (FcR) on NK cells. Multiple efforts presently aim to strengthen the efficacy of therapeutic mAb by modifying the ability of their Fc parts to induce ADCC. Another strategy is the development of bispecific antibodies which, after binding to their target antigen on tumor cells with their target arm, mediate a more focused immune response by stimulating specific activating receptors on cytotoxic lymphocytes with their effector arm. An important asset for the development of novel antibody constructs is the identification of suitable (ideally tumor-restricted) target antigens. We plan to develop bispecific immunoreceptor fusion proteins which, alike previously developed Fc-optimized immunoreceptor (NKG2D, GITR and RANK)–IgG1 fusion proteins, bind to the target antigens RANK ligand, GITR ligand and NKG2D ligands. However, instead of an Fc part the new constructs will contain antibody fragments directed against CD16 or CD3. The first precludes triggering of inhibitory FcR by rectricting stimulation to the activating CD16 receptor. The CD3 constructs allow for activation of T cells with their superior effector function, but require careful analysis of potential unspecific/side effects. The constructs will be functionally characterized using transfectants and primary leukemia cells in vitro and in immunodeficient mice after engraftment of primary leukemia cells and adoptive transfer of healthy autologous patient PBMC. Thus, the overall goal of the project is the development and preclinical characterization of novel antibody constructs for reinforcing NK and T cell immunity in patients with leukemia.


Associated Member: Barbara Schörg (PhD)

Name:

Barbara Schörg

Project:

B06

Supervisor:

Bernd Pichler

Email

Opens window for sending emailbarbara.schoerg(@)med.uni-tuebingen.de

Associated:

01.02.2014 -

Abstract:

Development of a new combined immunotherapy for cancer

Tumor antigen-specific T cells mediate strong anti-tumoral effects in mice and in humans and play a major role in novel cancer treatment strategies. To date most immunotherapies against cancer focus on CD8+ cytolytic T cells as they directly can destroy cancer cells. But Interferon-y (IFN-y) producing CD4+ T helper (Th1) cells, which are considered to provide only bystander help during anti-tumoral immune responses, gain more and more importance in the context of immunotherapies. 

Both malignant cells as well as immune cells express inhibitory checkpoint receptor/ligand pairs interfering with anti-tumoral T cell functions to promote tumor growth. Manipulation of these checkpoint pathways by blocking receptors or ligands such as lymphocyte activation gene 3 (LAG-3) and programmed death ligand 1 (PD-L1) with specific antibodies restores T cell functions. The goal of my project is to examine the efficacy and mechanisms of a combined CD4+ T cell and LAG-3/PD-L1 antibody based immunotherapy in mice with advanced endogenous or exogenous carcinomas and consequently to establish a novel highly efficient Th1 cell and checkpoint inhibitor-based combined immunotherapy. In addition, we aim to identify the exact sites of T cell activation and the sites of T cell effector functioning by non invasive in vivo bioluminescence optical imaging. T cell tracking studies will uncover how checkpoint inhibitors impair T cell migration patterns.

Associated Member: Nadine Simon

Name:

Nadine Simon

Project:

C01

Supervisor:

Jürgen Bauer

Email:

Opens window for sending emailn.simon(@)student.uni-tuebingen.de

Status:

PhD-student

Associated:

01.05.2014 -

Abstract:

IFN-γ- and TNF-producing TH1 cells that are specific for the tumor antigen Tag restrain Tag-induced islet cancers in mice expressing Tag under the control of the rat insulin promoter in all pancreatic islet cells (RIP-Tag2 mice). Tag expression causes invasive β-cell cancers in 2% of the islets by incomplete Rb suppression and p53 silencing. As hyperphosphorylation of Rb suppresses E2F genes, genes that accelerate gene transcription, we speculated that the cell cycle arrest that results from the senescence caused by the Th1 immunity stabilizes the genome of β islet cancer cells and reduces the chromosomal copy number aberrations. Indeed, comparative genomic hybridization (CGH) evealed quantitative chromosomal aberrations in cancers of sham-treated RIP1-Tag2 mice. In contrast, β-cell cancers treated with Tag-Th1 cells remained genomically stable. The aim of my project is to substantiate by performing CGH, whole exome sequencing, and epigenetic analysis whether senescence really stabilizes the genome.


Associated Member: Monika Stieglbauer

Name:

Monika Stieglbauer

Project:

DKTK (German Cancer Consortium)

Supervisor:

Stefan Stevanović

Email

Opens window for sending emailmonika.stieglbauer(@)student.uni-tuebingen.de

Status:

PhD-Student (Pharmacist)

Associated:

15.08.2012 - 

Abstract

Innovative Peptide Vaccines

The results of the C05-project members lead to tumor-specific peptides, which are promising candidates for patient-individual immunotherapy by vaccination. 

To make real patient-individual therapies possible, we and our cooperators want to establish a procedure, which allows the steps from tumor-tissue to vaccine as quick as possible.   

To save the quality for those potential pharmaceuticals and to make clinical trials possible, GMP is statutory. This for example includes well-regulated production-flows, risk management and several quality controls like mass spectrometry, HPLC (high performance liquid chromatography) and many others. One goal for instance is to establish a HPLC-method, which allows defined identification of single peptides in peptide-cocktails to control content and purity of each single peptide.

 

 


Associated Member: Fabian Vogt

Name:

Fabian Vogt

Project:

DKTK (German Cancer Consortium)

Supervisor:

Gundram Jung

Email

Opens window for sending emailfabianvogt(@)gmx.net

Status:

PhD-Student

Associated:

15.08.2013 - 

Abstract

Development of improved antibodies for the treatment of prostate cancer

The aim of this project is the development of optimized PSMA (prostate specific membrane antigen) antibodies with improved capability to recruit Fc receptor positive cells or t cells.During the last years the field of the development and clinical application of antibodies increased rapidly. Monoclonal antibodies are currently successfully used for the treatment of some forms of cancer. Rituximab (anti-CD20) for example, improved the therapy of malignant lymphoma.

In general, the specificity and effectiveness of such monoclonal antibodies have to be improved further. 

The aim of our group is to develop improved mono- and bispecific antibody formats directed against PSMA for cancer therapy. PSMA is almost exclusively expressed in normal prostatic epithelial cells and strongly overexpressed on prostate cancer cells. PSMA levels closely correlate with disease grade. Although the highest levels of PSMA expression are associated with high-grade, hormone-refractory and metastatic prostate cancer. This occurrence makes PSMA an interesting and promising target in prostate cancer therapy. 

 


PhD scholarship holder: Katharina Wolter
Associated Member: Katharina Wolter

Name:

Katharina Wolter

Project:

C13

Supervisor:

Lars Zender

Email

Opens window for sending emailkatharina.wolter(@)student.uni-tuebingen.de

Scholarship:

01.11.2013 - 31.10.2014

Associated:

01.11.2014 -

Abstract:

Senescence induction as an immunotherapeutic approach for the treatment of solid tumors

 

Cellular senescence is a stress response program that can be triggered by various stressors, such as telomere shortening, DNA damage or the aberrant activation of an oncogene. Senescent cells display characteristic changes in morphology and cell metabolism, but importantly, senescent cells also acquire a senescence associated secretory phenotype (SASP). It is now well established that senescence represents an important barrier against tumor development in vivo. Apart from arresting the growth of developing tumors, it was recently shown that SASP factors can trigger potent anti-tumoral immune responses. 

The therapeutic induction of senescence, and in particular the senescence associated secretory phenotype, may therefore represent a powerful immunomodulatory and immunotherapeutic approach for the prevention and treatment of cancer. The aim of my thesis is to explore strategies to therapeutically induce senescence in different tumor types and to characterize the nature of the immune response involved in the clearance of senescent tumor cells in vivo.


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