Effect of melanoma associated endothelial activation on inflammation, immune cell reactivity and tumour progression

Prof. Martin Schneider (Universitätsklinikum Mannheim), Prof. Viktor Umansky (DKFZ) 

Melanoma has a very high propensity to metastasize which is mainly responsible for the high tumour related mortality. Although little is known about the interaction between melanoma cells and microvascular endothelial cells, malignant cells need to overcome the endothelial cell (EC) layer.

The aim of the project is to study the production of pro-inflammatory and pro-coagulatory factors by ECs induced by melanoma cells and their effects on the immune cell reactivity and melanoma cell adhesion. Additionally the effect of the von Willebrand factor (involved in coagulation) on the effector T cells and myeloid-derived suppressor cells infiltrating skin tumours of ret transgenic mice will be studied. The ret transgenic mouse melanoma model closely resembles human disease as to tumour genetics, histopathology and clinical development.

Monocytes and tumor-associated macrophages in skin malignant melanoma

Dr. Markus Feuerer (DKFZ), Prof. Viktor Umansky (DKFZ)

Malignant melanoma is notorious for aggressive clinical behavior, proclivity for distant metastasis and poor response to currently available therapeutics. Melanoma has a well-known intrinsic immunogenicity but nevertheless clinical immunotherapeutic trials are not satisfactory due to the formation of a complex immunosuppressive network induced by the chronic inflammation developing in the tumour microenvironment.

Monocytes are important players in many diseases with an inflammatory component, such as infectious diseases, type I diabetes, atherosclerosis and cancer. The existence of at least two phenotypically and functionally different monocyte subsets has been demonstrated in human and mice, suggesting evolutionary conservation of monocyte heterogeneity. The subsets can be distinguished by differential surface marker expression and other features into classical (“inflammatory”) and non‐classical (“resident”) monocytes. Preliminary data shows that both monocyte subsets are present in the tumor tissue. But the origin and function of tumor-associated macrophages (TAMs) and tumor resident monocytes are not well understood.

Interaction of Human Papillomavirus (HPV) and Inflammation in Head and Neck Squamous Cell Carcinoma (HNSCC)

Dr. Jochen Hess (DKFZ), Dr. Angelika Riemer (DKFZ), Dr. Bladimiro Rincon-Orozco (DKFZ)

Human Papillomavirus 16 (HPV-16) has been identified as the causative agent of 50% of cervical cancers and many other HPV-associated tumours. It has been shown that local inflammatory cytokines are beneficial for the generation of anti-HPV effector T cells, and that HPV interacts with cytokine expression, but how inflammation and HPV interact is not fully understood. With the following experiments a deeper understanding of the processes will be achieved:

·Comparison of the expression of inflammatory mediators in HPV-driven and HPV-independent HNSCC (in tissue samples and cell lines)

·Analysis of several epigenetic mechanisms implicated in the regulation of different biomarker candidates in HPV driven carcinogenesis

·Analysis of the effects of identified modulators on the HPV epitope repertoire presented by MHC-I in HPV-driven tumors

·Establishment of animal model for the study of HPV-driven HNSCC

Immune cell function, energy homeostasis and cancer

Dr. Markus Feuerer (DKFZ), Prof. Stephan Herzig (DKFZ) 

Obesity is tightly associated with increased cancer risk, including pancreatic, colon, and liver tumours and it is considered as a state of chronic inflammation. Inflammation in turn has been shown to interfere with nutrient and hormonal signaling, thereby promoting metabolic dysfunction.

It is hypothesized that inflammatory reactions in adipose tissue determine tumour susceptibility under conditions of metabolic dysfunction. Therefore, it is aimed to define the impact of differential immune cell recruitment and activation on adipose tissue function and cancer development.

·Aim 1: Test the influence of distinct T cell populations on adipocyte energy homeostasis and endocrine function in vitro.

·Aim 2: Define mechanisms of adipocyte-tumor cell interaction in vivo.

Function of S100-RAGE signalling and Natural Killer cells in inflammation-associated cancer

Prof. Peter Angel (DKFZ), Prof. Heidi Cerwenka (DKFZ), Dr. Jochen Hess (DKFZ)

Hepatocellular carcinoma (HCC) is the most frequent type of liver cancer and one of the most prevalent causes of cancer mortality worldwide. These tumours arise at sites of chronic liver injury, inflammation, and hepatocyte proliferation provoked by several causes. In HCC and liver damage, Natural Killer (NK) cells are central innate immune cells that, remarkably, represent up to 40% of the lymphocyte population in liver. It has been shown in other tumour entities that peripheral NK cells greatly differ from tumour-infiltrating NK cells, in the way that the latter show an immature phenotype. Now the role of NK cells in inflammation-associated liver cancer will be investigated. More precisely the following questions will be approached:

·Do oval cells (OC) affect NK cells during chronic liver damage, inflammation and HCC? Does this depend on RAGE-dependent OC activation by RAGE ligands (S100, HMGB1)?

·Are NK cells increased in number during liver damage and HCC? How do they differ phenotypically and functionally from NK cells from healthy livers?

·How do S100A8/A9 and (maybe later HMGB1) produced locally by tumour cells alter the recruitment, composition, activation of tumour infiltrating immune cells?

·What is the role of NK cells in tumour surveillance in HCC and liver damage?

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