Pathophysiological Concept, Current, and Previous Topics

(1) Dichotomy of inflammation-associated carcinogenesis in colitis

A major discussion is going on about the dichotomy of carcinogenesis either evolving from inflammation-induced cancer or cancer-induced pro-tumor inflammation. In different projects we try to elucidate the nature of inflammation-induced carcinogenesis which can be e.g. based on a pro-tumorigenic Th2 driven inflammation or pathological crypt remodelling in the course of chronic inflammation. On the other hand, emerging tumors are able to escape the immune system or even modulate it for their own advantage. We have found, that sphingolipids, especially S1P lyase are major contributers to this dichotomy. With the help of e.g. CRISPR/Cas9 we modulate the sphingolipid-axis in hematopoietic cells or colon tissue cells and investigate the impact on disease etiology, crypt remodelling or metastasis. Furthermore, we hypothesize that the dual roles of anticarcinogenic and immunomodulatory natural products formulated in nanoemulsions may supplement cancer immune therapy.

(2) Pathogenesis of Systemic Sclerosis – involvement of sphingolipid signaling

Systemic Sclerosis (SSc) is a clinically heterogeneous autoimmune and connective tissue disease affecting the skin and several inner organs. Its pathophysiology is mainly characterized by microangiopathies, inflammation and fibrosis. This project is based on the assumption that endothelial cells are major players during early vascular and dermal fibrogenesis, as well as the fact that inflammatory and fibrotic processes can be modulated by the bioactive sphingolipid sphingosine-1-phosphate (S1P) and its metabolites. With the help of in vitro and in vivo- studies, we investigate the function of S1P signaling during fibrogenesis. Supplementary, the analysis and clinical correlation of sphingolipid profiles in samples of SSc patients should contribute to a better understanding of the complex and heterogeneous disease.

(3) Modulation of IL-1/ IL-33 TIR signaling and its role for antigen-specific cytotoxic T lymphocytes

Cancer immune therapy is based on the detailed understanding of the competition of tumor cells thriving to survive and the anticancer activity of the innate and adaptive immune system. While currently co-inhibitor blockade is in focus of clinical trials, the use of adjuvants typically acting through TLRs and signaling pathways of dendritic cells has already been used by Paul Ehrlich‘s first „cancer vaccinations“.
In this PhD project we like to follow-up on a pathway very closely related to the TLR/adjuvant, namely the TLR-like signaling pathways of IL-1, IL-33 and other IL-1 family members, called TIR. So far, investigations of pro- versus anticancer effects of IL-33 yielded contradictory results, especially considering the undefined role of the soluble IL-33 receptor sST2. While IL-33 is acting locally and very short-lived, sST2 has been attributed to cancer and fibrotic processes by us and others. Recently we have shown that IL-33 and IL-12 synergistically enhanced CD8 activity, and – introducing another modulator – that S1P may exhibit CD8 inhibitory, pro-cancer properties. Therefore, in a multicellular cytotoxicity assay setting, comprising dendritic cells, CD4, CD8 and Treg, as well as tumor antigen-bearing melanoma and colon cancer cells, we plan to analyse the regulation of IL-33 anticancer bioactivity and the influence of S1P.

(4) Kynurenine Metabolism in Colitis – Biomarker for Inflammation and Carcinogenesis

Crohn's disease and ulcerative colitis are chronic inflammatory bowel diseases (IBD). The immune pathogenesis leads to a perpetuating mucosal inflammation based on an imbalance of pro- and anti-inflammatory cytokines. In this project the metabolic profile of the tryptophan degradation in patients with the suspected diagnosis IBD and patients before diagnosis, with relapse or in remission are compared to a healthy cohort. The project objective is to develop a biomarker matrix, e.g. tryptophan / kynurenine ratios, for a clear diagnosis, a better assessment of the stage of the disease and to control of the success of the therapy. Furthermore, more details of the biological function of additional tryptophan metabolites will be explored in a multi-cellular model. The influence of intra- and transcellular metabolism of different cell types (e.g. immune cells, enterocytes, bacterial cells and cancer cells) should be resolved in order to develop new molecular targets and therapeutic approaches.

(5) Chronic inflammation and chemokines

Nadine Ogrissek, Oliver Giegold

During an immune response certain chemokines are especially important for extravasation of T cells into inflamed tissue. An upregulated inflammatory chemokine receptor signaling is known to be involved in the pathogenesis of autoimmunity. Therefore these receptors are promising targets for the treatment of chronic inflammatory disorders like type-1-diabetes, multiple sclerosis or psoriasis. However, single chemokine receptor antagonists or anti-chemokine antibodies often missed final approval for a clinic application. Our recent investigations contributed to the understanding of the underlying reasons, e.g. redundancy, systemic application and heterologous interaction of homing and inflammatory chemokines. Thus, we decided to develop a cell-based therapy for chronic inflammation with a treatment that is not only based on the effect of chemokine receptor antagonists combinations, but moreover on a localized, and “on demand“ release by means of TCR-activation-dependent antagonist expression.Our methodological arsenal encompasses conditional lentiviral vector cloning, lymphocyte transduction, FACS sorting, and dynamic flow chamber assays.

(7) Redox regulation of chronic inflammation and carcinogenesis

Cornelia Richter, University Clinic Dresden; Martina Herrero San Juan and Heinfried H. Radeke

On the background of the simple enigma how dendritic cells may either prevent or support chronic inflammation dependent cancerogenesis we have been investigating differential TLR signaling pathways leading to either IL-12 or IL-23. Among other factors the balance between IL-12 and IL-23 modulates chronic colon inflammation and colon cancer. Based on previous mouse colitis studies we now established a colitis associated colon cancer model. Technically equipped with a mouse coloscopic, computer-aided system we are monitoring the progress of colitis and the development of tumor growth. IL-12 deficient mice develop less colitis, but are more susceptible to cancer. Additionally, in vitro we have shown that the NADPH oxidase protein p47phox down regulates IL-12 in dendritic cells. Currently we are focusing on the impact of p47phox redox and redox-independent regulation of IL-12 and IL-23 in the colitis/cancerogenesis mouse model (Cornelia Richter, Martina Herrero San Juan).
In a second project we acknowledge newly developing concepts in cancer therapy. Cytostatic agents that simultaneously exhibit immune stimulatory activity hold a great promise as a novel approach for an integrated cancer therapy. Therefore, one cooperative international project aims to investigate phytocompounds and S1P analogs regarding their antitumor activity on melanoma cells and their immune modulating effect on primary dendritic cells and T cells (Corina Danciu, Cristina Dehelean, Elisabeth Katzy, Katja Rueger, Kathrin Pfarr, Kathrin Zych; also see continuation of the project by Dr. A. Schwiebs above).