SFB 1292:  Targeting convergent mechanisms of inefficient immunity in tumors and chronic infections

• Subject Area: Medicine ; Biology
• Term: since 2018
• Website: Homepage
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 318346496

The immune system collectively functions to recognize and protect tissues from infections, damage or malignant transformation. Appropriate innate and adaptive immune system interactions lead to highly efficient recognition and clearance of pathogens or transformed cells. Maladaptive interactions between these two systems however can result in harmful immunologic responses including chronic infections and development of cancer. Understanding the mechanisms behind these maladaptations, which share specific features with ineffective immunity in chronic infections, is crucial for achieving therapeutic benefits. Our goal here is to deploy a wide array of interdisciplinary approaches in order to perform a systematic, comparative, multi-layered and integrative analysis of the mechanisms responsible for inefficient immune responses, which are expected to provide novel therapeutic avenues for the restoration of efficient immunity in both, tumors and chronic infection. Starting in 2018, we investigated how inappropriate function of the innate immune system affects adaptive immunity and contributes to inefficient anti-cancer immunity and chronification of infections. A special focus was placed on the role of tumor cell-derived factors, small molecule-based modulation of signaling pathways and the contribution of surface molecules or soluble mediators, like cytokines and coagulations proteases. Key findings of the first funding period describe the important contribution of tissue acidification, secreted factors and receptors of the coagulation system, metabolic reprogramming of cells and even far-fetching effects like microbiome-induced tonic type-1 interferon levels on the control of pathogen- and tumor-specific immune responses.We are now planning to further understand in detail how soluble mediators contribute to immune dysfunction and how this can be regulated to gain therapeutic benefits. We also want to achieve a better understanding of the role of the microbiome and microbial metabolites as well as tissue acidification as a consequence of enhanced aerobic glycolysis. Our observations from the initial funding period suggest that the aforementioned factors crucially contribute or interfere with systemic adaptive immune responses. To better appreciate the cellular crosstalk in tumor-, persistently infected and healthy tissue, we will develop new methods, which genuinely reflect the heterogeneity of tumors and infected tissues and allow a spatial resolution of different cell populations from both, mouse and human tissues. All of this will lead to an unprecedented comparative analysis of the various immune evasion mechanisms in cancers and in chronic infections. This will result in a detailed map of common and disease-specific immune escape checkpoints and provide the basis for future stratified therapies allowing the development of precision medicine to treat chronic infections and cancer.

• DFG Programme: Collaborative Research Centres

Current projects

• 01 - Understanding the role of GPCR65-dependent metabolic communication in the tumor microenvironment (Project Heads Bopp, Tobias ;  Schmitt, Edgar )
• 02 - TF-PAR2 signaling in viral infections (Project Heads Beling, Antje ;  Ruf, Wolfram )
• 04 - Regulation of SAMHD1: impact on inflammation, viral replication and malignant diseases (Project Head König, Renate )
• 05 - Signaling mechanisms regulating anti-tumor immunity and viral pathogenesis (Project Heads Ciesek, Sandra ;  Rajalingam, Krishnaraj )
• 06 - Molecular T cell immunotherapy and inhibition of tumor immune escape mechanisms (Project Heads Munder, Markus ;  Theobald, Matthias )
• 08 - Modulating macrophages and platelets in hepatocellular carcinoma and infection (Project Heads Deppermann, Carsten ;  Schuppan, Detlef ;  Sprinzl, Martin )
• 09 - Modulation of glioma-neuron networks by immune cells in malignant brain tumors (Project Heads Schmidt, Mirko H.H. ;  Zipp, Frauke )
• 10 - Coagulation signaling as a modulator for anti-tumor immunity (Project Heads Graf, Ph.D., Claudine ;  Ruf, Wolfram )
• 11 - Regulation and host targets of viral immune evasion (Project Heads Distler, Ute ;  Lemmermann, Niels ;  Reddehase, Matthias J. )
• 12 - Targeting chromatin complexes to reverse AML immune escape for engineered cell therapy (Project Heads Fulda, Simone ;  Kühn, Michael ;  Ullrich, Evelyn )
• 13 - Microbiota induced tonic type I interferons in the control of CTL responses to cancer, chronic and acute virus infections (Project Heads Probst, Hans Christian ;  Schild, Hansjörg )
• 15 - Mechanisms controlling Th17 and regulatory T cells in the anti-Leishmania response (Project Heads von Stebut-Borschitz, Ruth Esther ;  Waisman, Ari )
• 16 - Linking the intestinal microbiome and immune mediated effects to primary tumor growth and therapy (Project Head Greten, Florian R. )
• 17 - Neo-epitope specific CD4+ T cells – Anti-tumoral mechanisms and their modulation (Project Heads Kreiter, Sebastian ;  Sahin, Ugur )
• 18 - Therapeutic blockade of Regulatory T cells (Project Head Sparwasser, Tim Dominik )
• 19 - Induction of a tissue repair program as a strategy for immune evasion in tumors and chronic infections (Project Heads Delacher, Michael ;  Marini, Federico )
• 20 - Mechanisms of IL-10 mediated tumor immune evasion in colorectal cancer development (Project Heads Clausen, Björn ;  Hövelmeyer, Nadine )
• 21 - Type-I Interferons – a double-edged sword in Myeloproliferative Neoplasms and Chronic Viral Infections (Project Heads Muth, Sabine ;  Radsak, Markus P. )
• 22 - (Re)installing Cancer Immunity in pancreatic cancer and cancers of the upper GI tract (Project Heads Gaida, Matthias ;  Türeci, Özlem )
• MGK - Integrated Research Training Group (Project Heads Bopp, Tobias ;  Clausen, Björn )
• Q01 - Integrated OMICS, Bioinformatics and Morpho-molecular Immunomonitoring Unit (Project Heads Albrecht, Christian ;  Bukur, Valesca ;  Gaida, Matthias ;  Tenzer, Stefan )
• Z02 - Central Task (Project Head Schild, Hansjörg )

Completed projects

• 07 - Defining the role of hepatocellular carcinoma-related epigenetic alterations driving immune evasion (Project Heads Marquardt, Jens U. ;  Strand, Susanne )
• 14 - Immunmodulation of cytomegalovirus latency and reactivation by regulatory T cells and dendritic cells (Project Heads Clausen, Björn ;  Holtappels, Rafaela )

• Applicant Institution: Johannes Gutenberg-Universität Mainz
• Participating University: Charité - Universitätsmedizin Berlin; Goethe-Universität Frankfurt am Main; Technische Universität Dresden; Universität zu Köln
• Participating Institution: Georg-Speyer-Haus; Institut für Tumorbiologie und experimentelle Therapie; Paul-Ehrlich-Institut; Bundesinstitut für Impfstoffe und biomedizinische Arzneimittel
• Spokesperson: Professor Dr. Hansjörg Schild