TGF-β is a pleiotropic cytokine, which influences the progression of cancer in many respects. On the one hand it is a potent growth inhibitor and inducer of apoptosis to most cell types, leading to the fact that TGF-β has been considered a tumour suppressor for a long time. On the other hand TGF-β promotes cellular migration, invasion and epithelial-mesenchymal transition. Moreover TGF-β induces a systemic suppression of the immune system and represents one of the most prominent components of the tumour microenvironment, leading to the assumption that TGF-β could play a major role for the inhibition of anti-tumour immune responses. This hypothesis is supported by the finding that TGF-β is required for the development of induced regulatory T-cells, which are thought to represent an important obstacle for the immune-mediated elimination of cancer cells. Furthermore, TGF-β is involved in the differentiation of Th17 cells that also seem to play a role for tumour development, according to recent reports.
The exact mechanisms of TGF-β dependent regulation of anti-tumour immune responses, in particular in lung cancer, are still not completely understood and are the subject of this study. To analyse the influence of TGF-β on lung tumour infiltrating CD4+ T-cells we use an experimental mouse model of lung carcinoma on wild-type mice as well as mice, which exhibit defective TGF-β signalling in T-cells. Additionally we use human samples for mRNA as well as protein analysis to characterize the differential expression of TGF-β regulated genes.
Project manager: Katerina Andreev, M.Sc.
The MP-IL-35 study represents a collaboration between Department of Thoracic Surgery and Department of Molecular Pneumology in partnership with Institute of Pathology and Department of Anesthesiology, University Hospital Erlangen. The aim of this study is to investigate the immunological and molecular basis in patients with non-small-cell lung carcinoma. Different analyzes are carried out on human tissue of lung cancer patients who undergo thoracic surgery. One focus of the study is to analyze the role of interleukin-35 (IL-35) in lung cancer, a cytokine that is secreted by regulatory T cells. To elucidate this question, we examine the IL-35 producing cells in tumoral, peritumoral and normal lung tissue. Furthermore, the localization of IL-35 producing cells in the lymph node and the concentration of IL 35 in the broncho-alveolar lavage fluid (BALF) and serum are analyzed.
Project manager: Dr. med. Denis Trufa
Interleukin 2 (IL‑2) is a type 1 cytokine which is mainly produced by T cells upon antigen stimulation. CD4+ and CD8+ T cells are very important for the anti-tumor immune response as they secrete effector cytokines which enhance the immune system to fight against tumor. In addition, CD8+ T cells are able to kill tumor cells directly by secreting cytotoxic granules. The receptor for the cytokine IL‑2 consists of the IL‑2Ra (CD25), IL2Rb (CD122) and IL2Rg (CD132/gc). The three subunits together form the high-affinity IL‑2R. CD25 is important for the binding affinity of IL‑2 whereas CD122 and CD132 mediate the intracellular signaling. IL‑2 induces in T cells the proliferation and development into Th1 and Tc1 cells. Its effect on tumor infiltrating regulatory T cells (Treg), which are known to suppress the immune system, is not fully understood. The treatment for lung cancer patients involves, beyond removal of the tumor during surgery and chemotherapy, also immunotherapies. In some cancer types the application of the cytokine interleukin-2 (IL‑2) is used as therapy, but this often has some toxic side effects for the patients. In this project we want to investigate the role of IL‑2 signaling in lung cancer. Therefore we use material from lung cancer patients as well as murine models of lung tumor. We analyze the effects of IL‑2 on tumor-infiltrating T cells of the lung to figure out how IL‑2 modulates T cell immune responses in the tumor milieu of lung cancer and to generate ideas for potential IL‑2 mediated immune therapies for lung cancer patients.
The transcription factor nuclear factor of activated T cells (NFAT) has been originally described as a nuclear protein which binds to the human IL-2 promoter. The family of NFAT-proteins consists of five members, which have similar structural elements and DNA-binding domains. Predominantly NFATc1 and NFATc2 are highly expressed in T cells and activate the human IL-2 and IL-4 promoter. This leads to the assumption that the calcium-regulated Calcineurin/NFAT-signalling cascade controls T cell activation and peripheral tolerance. We are investigating the role of Nfatc1 in lung cancer. Because NFATc1-deficiency is embryonic lethal, we analyse conditional Nfatc1-deficient mice, which have a NFATc1-deficiency only in CD4+ and CD8+ cells. Therefore we use a murine model of lung carcinoma to analyze the influence of NFATc1 on T cell associated anti-tumor immune responses.
The inflammatory cytokine IL-6, which is activated during the early immune response, belongs to the family of cytokines whose signal transduction is dependend on the transmembrane protein gp130. After binding of IL-6 to a soluble or a membrane bound IL-6 receptor (IL-6R) , gp130 dimerizes and triggers a signal cascade which leads – among other things - to the phosphorylation of STAT3. Nearly all cells of the body express gp130 on their surface, while IL-6R is primarily expressed on hepatocytes, neutrophils, monocytes/macrophages and some B- and T cell compartments. IL-6 possesses pro- and anti-tumoral effects. STAT3 is only temporarily activated in normal cells, whereas in lung-tumor cells and other tumor cells it is continuously activated. Phosphorylated STAT3 transactivates anti-apoptotic proteins and promotes cell proliferation. Patients with lung canecr show increased levels of IL-6 in the blood. We are working on investigating the role of IL-6 in a murine model of the lung adenocarcinoma.
The role of "Signal Transducer and Activator of Transcription protein-3" (STAT3) in non-small cell lung cancer (NSCLC) (Lisanne Heim)
The role of STAT5 in non-small cell lung carcinoma (NSCLC)(Juliane Friedrich)
The role of IL-10 in lung cancer (Julius Vahl)
The role of acid sphingomyelinase in non-small cell lung carcinoma (Maximilian Bailer)