Group Groettrup

Research topics

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Development of an immune therapy for prostate cancer

Prostate carcinoma (CaP) is becoming an increasingly severe health problem for men in industrialized countries. Due to an enhanced life expectancy and a more intensified clinical scrutiny, CaP has become the most frequently diagnosed cancer in men. The probability of disease is 10% and the risk of dying from CaP is 3%, i.e. about 40'000 men die from CaP every year.

After the formation of metastases, carcinoma growth can be suppressed during several months by hormone ablation therapy in most cases. Unfortunately, male sex hormone-independent tumor growth develops in most cases after 1-2 years. There is no effective therapy for these hormone refractory CaP tumors till now, and even the newest achievements in chemotherapy reveal modest life-prolonging effects only. For that reason, we have been developing a prostate cancer immune therapy for seven years now. The aim of this immune therapy is a systematic fortification of the patient's own immune defence against the carcinoma in a way that helps the recognition and killing of tumor cells by so-called T killer cells. A big advantage of immune therapy is the high specificity for tumor cells, whereas only minor side effects are expected to occur. Another advantage is that immune cells patrol the body and are thus able to find and eliminate distant metastases. At present immune therapies are in development for clinical trials but the techniques still have to be improved in order to evoke strong enough immune responses in patients. Up to now success in immune therapy is still restricted to a minority of patients. We conducted a phase I clinical trial in collaboration with the Departments for Oncology and Urology at the Cantonal Hospital of St. Gallen using dendritic cells (DC) grown from patients' blood that were loaded with tumor antigens and re-injected into the patients. Using this technique, immune responses against tumor antigens were induced in some patients resulting in a termination or attenuation of disease progression. However, DC generation is laborious and expensive, rendering a clinical application on a large scale rather improbable. At the BITg, we will look for new strategies to deliver tumor antigens to patients' DC by subcutaneous injection in a way that they can be readily taken up by the DC. A laborious cultivation of DC could thus be avoided. In collaboration with the Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich (PD Dr. Bruno Gander), we are developing techniques to improve the encapsulation of tumor antigens together with DC maturation stimuli and chemokines into biodegradable poly(D,L-lactide-co-glycolide) (PLGA) microspheres (Fig. 2).



After microsphere uptake (Fig. 3), DC migrate into lymph nodes (please refer to the projects of Daniel Legler's group), where they stimulate tumor combating T lymphocytes. We could already demonstrate that microsphere uptake by DC does not alter their biological properties and that incorporated antigens can be presented on MHC class I as well as MHC class II molecules over a prolonged period of several days.



Another aim of our research is the identification of new target antigens for prostate cancer immune therapy. Up to now mainly self-antigens present in the normal prostate as well as in tumor tissues are used. We intend to look for new CaP antigens by making use of the antigen specificity of T killer cells in order to identify novel tumor antigens.

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The biochemistry and function of FAT10 - an MHC encoded and cytokine inducible ubiquitin-like protein

FAT10 (HLA-F-associated transcript 10) was identified by sequencing of the human MHC class I locus and belongs to the family of the ubiquitin-like modifiers. FAT10 is a protein of 18 kDa consisting of two ubiquitin-like domains in a head to tail arrangement, separated by a short linker. Although it was initially reported to be expressed in mature B cells and dendritic cells only, FAT10 can be synergistically induced in cell lines from virtually all tissues with the proinflammatory cytokines IFNγ and TNFα. Interestingly, induction of FAT10 expression leads to cell death by apoptosis within 2 days. Furthermore FAT10 is up-regulated in cancers of liver and colon probably due to the IFNγ and TNFα production of the tumor environment and it plays a role in the regulation of chromosomal stability. FAT10 can be covalently conjugated to so far unidentified target proteins via its C-terminal diglycine motif and FAT10ylated proteins become degraded by the proteasome or are transported to aggresomes where they become degraded by autophagy. Currently we are characterizing putative E2 enzymes as well as E3 ligases possibly involved in the FAT10 conjugation pathway which we identified by doing a yeast 2 hybrid screen with FAT10 as a bait protein. In addition, to gain more information about the role of FAT10 e.g. in cancer, autophagy or apoptosis we are currently screening for substrates that become FAT10ylated.