Two new research grants by Berliner Krebsgesellschaft
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The Berliner Krebsgesellschaft will fund two very interesting research projects by Dr. Linda Feldbrügge and Dr. Karl Hillebrandt in collaboration with Dr. Björn Papke.

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„Purinergic immune regulation in peritoneal metastases of gastric cancer via CD39 and ENTPD3 – target for a novel immune Checkpoint inhibition?“ – PI: Dr. Linda Feldbrügge

Peritoneal metastasis, especially derived from gastric cancer (GC), has a poor prognosis with a median survival of only months. Treatment is usually confined to palliative systemic chemotherapy, complemented individually by checkpoint inhibitors that block PD1-signaling. Innovative therapies combining surgery with local drug application such as hyperthermic intraperitoneal chemotherapy (HIPEC) or pressurized intraperitoneal aerosol chemotherapy (PIPAC) are still pending confirmation in clinical trials. Purinergic signaling, which involves ATP hydrolysis and generation of adenosine, regulated through CD39 (ENTPD1) and related enzymes, has been recognized as a critical immunoregulatory pathway in the tumor microenvironment (TME). The objective of the current project is to characterize the immune environment in the unique setting of peritoneal metastasis of gastric cancer with a focus on ectonucleotidases CD39 and ENTPD3 on T cells, macrophages and MDSC as well as mechanisms of ectonucleotidase-mediated immune regulation in tumor associated macrophages in vitro. As a high-volume center for surgical therapy of peritoneal malignancies and with years of experience in ectonucleotidase research, we aim to advance the understanding of peritoneal metastasis and contribute to improving treatment options for our patients.

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"The influence of decellularised tumour matrix heterogeneity in relation to KRAS/MAPK inhibition of in vitro colorectal liver metastases." PI: Dr. Karl Hillebrandt and Dr. Björn Papke (Dept. of Pathology)

Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide, with approximately 900,000 annual deaths. 30-50% of patients develop colorectal liver metastases (CRLM) during their disease. More than 50% of these tumors have mutations in the KRAS oncogene, making them usually poorly treatable. Despite multimodal therapy concepts have improved the outcome of these patients, a large proportion of patients suffer a recurrence of their disease. For better therapeutic concepts, we need to better understand the tumor biology and metastatic mechanisms of these diseases. In vitro models, such as two-dimensional cell culture, are primarily used for this purpose. These models can only reflect the physiological complexity to a limited extent. Recently, it was shown that the use of organ-specific and tumor-specific extracellular matrix (ECM) has an impact on the behavior of human CRC cell lines. Culture of cell lines with decellularized matrix resulted in cells adopting a metastatic cell state and forming significantly more metastases in a mouse model than cells cultured on plastic or collagen. The goal of our project is to study the growth (with and without inhibition of the RAS/MAPK signaling pathway) of patient-derived tumor organoids growing on different decellularized metastatic matrices (dMM) and decellularized liver matrices (dLM). These studies of tumor matrix heterogeneity are essential to define which starting materials, for in vitro modeling of our three-dimensional tumor organoid culture, can be used to develop the most physiological, personalized dLM/dMM-based CRLM in vitro model possible. Based on these results, we plan to conduct small-scale therapy evaluations for personalized tumor therapy using our in vitro dLM/dMM-based CRLM in the near future.

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Our manuscript "Depletion of donor dendritic cells ameliorates immunogenicity of both skin and hind limb transplants" has been accepted for publication in Frontiers in Immunology, section Alloimmunity and Transplantation. Authors are Muhammad Imtiaz Ashraf, Joerg Mengwasser, Anja Reutzel-Selke, Dietrich Polenz, Kirsten Führer, Steffen Lippert, Peter Tang, Edward Michaelis, Rusan Catar, Johann Pratschke, Christian Witzel, Igor M. Sauer, Stefan G. Tullius, and Barbara Kern.

Acute cellular rejection remains a significant obstacle affecting successful outcomes of organ transplantation including vascularized composite tissue allografts (VCA). Donor antigen presenting cells (APC), particularly dendritic cells (DC), orchestrate early alloimmune responses by activating recipient effector T cells. Employing a targeted approach, we investigated the impact of donor-derived conventional DC (cDC) and APC on the immunogenicity of skin and skin-containing VCA grafts, using mouse models of skin and hind limb transplantation.
By post-transplantation day 6, skin grafts demonstrated severe rejections, characterized by predominance of recipient CD4 T cells. In contrast, hind limb grafts showed moderate rejection, primarily infiltrated by CD8 T cells. While donor depletion of cDC and APC reduced frequencies, maturation, and activation of DC in all analysed tissues of skin transplant recipients, reduction in DC activities was only observed in the spleen of hind limb recipients. Donor cDC and APC depletion did not impact all lymphocyte compartments but significantly affected CD8 T cells and activated CD4 T in lymph nodes of skin recipients. Moreover, both donor APC and cDC depletion attenuated the Th17 immune response, evident by significantly reduced Th17 (CD4+IL-17+) cells in the spleen of skin recipients and reduced levels of IL-17E and lymphotoxin-α in the serum samples of both skin and hind limb recipients. In conclusion, our findings underscore the highly immunogenic nature of skin component in VCA. The depletion of donor APC and cDC mitigates the immunogenicity of skin grafts while exerting minimal impact on VCA.




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