The research group is interested in the characterization of cytotoxic- and regulatory properties of
γδ T lymphocytes and their role in tumor immunology with a focus on ductal pancreatic adenocarcinomas (PDAC) and ovarian carcinomas. Additionally, the group establish a method to determine the cytotoxic capacity of T lymphocytes in tumor tissue.
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Cytotoxic γδ T lymphocytes are an attractive subpopulation of T lymphocytes, which offer certain
advantages for novel strategies of T cell-based immunotherapy due to their plasticity in bridging innate and adaptive immunity. Cytotoxic lymphocytes can infiltrate into lymphomas and numerous epithelial tumors. Several γδ T lymphocytes recognize phosphorylated intermediates of the endogenous Mevalonate metabolic pathway in a HLA-independent manner. These intermediates often accumulate in tumor cells due to a dysregulation. The in vivo-relevance of human cytotoxic γδ T lymphocytes towards different tumor entities has already been demonstrated in various animal models as well as in clinical trials. Our recent studies in cooperation with Prof. M. Peipp (Divison of Antibody-Based Immunotherapy, UKSH, CAU Kiel) and Prof. S. Sebens (Institute of Experimental Cancer Research, UKSH, CAU Kiel) demonstrated that bispecific antibodies enhanced cytotoxicity designed of adoptively transferred γδ T lymphocytes against pancreatic tumors grafted into immunocompromized mice.
The activation of cytotoxic tumor-infiltrating T lymphocytes can be negatively influenced by e.g. an
immunosuppressive tumor environment, the accumulation of regulatory αβ- or γδ T lymphocytes in the tumor, different resistance mechanisms of the tumors or the induction of senescence/dormancy.
We examine the different immunosuppressive mechanisms that prevent an effective immune response of tumor-infiltrating γδ T lymphocytes and possibilities to enhance cytotoxic activity of tumor-infiltrating γδ T lymphocytes by the usage of bispecific antibodies and / or Toll-like receptor agonists.
In addition, a substantial aim of our studies is to investigate the phenotypic and genotypic γδ TCR repertoire and the functional anti-tumor capacity of tumor-infiltrating γδ T lymphocytes versus αβ T lymphocytes of fresh tumor tissue in comparison to T lymphocytes of autologous blood of pancreatic- or ovarian cancer patients.
All this work is performed in close cooperation with the DFG-funded research group FOR2799.
In this context, we developed a novel personalized method to analyze activation, check-point inhibitor expression, proliferation and cytotoxicity of tumor-infiltrating immune cells within the complete human freshly isolated tumor tissue and without separation of cells. This new preclinical method allows a short-time and personalized measurement of the capacity of patient’s immune cells to kill tumor cells, and thereby provides information about a possible cancer treatment in just a few days.
This preclinical method is used in different cooperation projects together with Prof. M. Peipp and/ or the companies Evobright GmbH (Vienna, Austria), Roche (Basel, Switzerland) and Biomunex Pharmaceuticals (Paris, France) to analyze different bispecific antibody constructs, which target γδ T lymphocytes, Mucosal-associated invariant T cells, NK cells or αβ T lymphocytes to solid tumors in an immunosuppressive tumor microenvironment.
Our research projects in cooperation with our different collaborators should provide better insights in the role of different immune cells (with a focus on γδ T lymphocytes) in anti-tumor response and help to optimize immunotherapies.
1. Schadeck J, Oberg HH, Peipp M, Hedemann N, Schamel WW, Bauerschlag D, Wesch D (2024). Vdelta1 T cells are more resistant than Vdelta2 T cells to the immunosuppressive properties of galectin-3. Front Immunol, 14:1286097.
2. Oberg HH, Janitschke L, Sulaj V, Weimer J, Gonnermann D, Hedemann N, Arnold N, Kabelitz D, Peipp M, Bauerschlag D, Wesch D (2020). Bispecific antibodies enhance tumor-infiltrating T cell cytotoxicity against autologous HER-2-expressing high-grade ovarian tumors. J Leukoc Biol, 107:1081-1095.
3. Oberg HH, Kellner C, Gonnermann D, Sebens S, Bauerschlag D, Gramatzki M, Kabelitz D, Peipp M, Wesch D (2018). Tribody [(HER2)2xCD16] is more effective than trastuzumab in enhancing γδ T cell and natural killer cell cytotoxicity against HER2-expressing cancer cells. Front Immunol 9:814.
4. Gonnermann D, Oberg HH, Kellner C, Peipp M, Sebens S, Kabelitz D, Wesch D (2015). Cyclooxygenase-2 expressing pancreatic ductal adenocarcinoma cells are resistant against γδ T cell cytotoxicity. OncoImmunol, 4: e988460.
5. Oberg HH, Peipp M, Kellner C, Sebens S, Krause S, Petrick D, Adam-Klages S, Röcken C, Becker T, Vogel I, Weisner D, Freitag-Wolf S, Gramatzki M, Kabelitz D, Wesch D (2014). Novel Bispecific Antibodies Increase γδ T-Cell Cytotoxicity against Pancreatic Cancer Cells. Cancer Res, 74: 1349-1360.
6. Shojaei H, Oberg HH, Juricke M, Marischen L, Kunz M, Mundhenke C, Gieseler F, Kabelitz D, Wesch D (2009). Toll-like receptors 3 and 7 agonists enhance tumor cell lysis by human γδ T cells. Cancer Res 69:8710-8717.
7. Wesch D, Beetz S, Oberg HH, Marget M, Krengel K, Kabelitz D (2006). Direct costimulatory effect of TLR3 ligand poly(I:C) on human γδ T lymphocytes. J Immunol 176:1348-1354.
Prof. Dr. rer. nat. Daniela Wesch
PD Dr. sc. hum. Hans-Heinrich Oberg
University Hospital Schleswig-Holstein
Institute of Immunology
Arnold-Heller-Straße 3
Haus U30
24105 Kiel