Junior group 'Coagulation factors in immunity'

PD Claudine Graf, MD PhD

Group leader

The coagulation system is an integral part of the innate immune defense against tissue injuries. During tumor diseases, systemic changes affect coagulation, platelet-leukocyte interaction, and immune responses. The cellular receptors of the coagulation proteases are "Tissue Factor (TF)" and the "Endothelial Protein C Receptor (EPCR)". They are structurally related to interleukin, CD1d and toll-like receptors (TLR) and are expressed e.g. by tumor, immune and vascular cells. They interact with the coagulation factors FX, FVII and protein C. In addition to their synthesis in the liver, FVII and FX are also expressed by macrophages and dendritic cells and influence their phenotypes. As a result, they also modulate anti-tumor immune responses.

We are interested in the control of macrophage and DC phenotypes mediated by coagulation proteases and platelet-leukocyte interaction. We are investigating this in the context of chronic inflammatory processes, especially malignancies, using mouse models that show special alterations in the expression or signaling of coagulation proteases. Translational relevance results from the synergistic effects of anticoagulants and checkpoint inhibitors observed in preclinical models on reducing tumor growth and improving the anti-tumor immune response.

Research interest

• Role of coagulation proteases in tumor immunity 
• Influence of coagulation factors on function of innate immune cells
• Influence of anticoagulants and checkpoint inhibitors on immune cells

Partners of collaboration

Partners at the University Medical Center Mainz

• Prof. Wolfram Ruf (CTH)
• Prof. Krishna Rajalingam (SFB 1292 TP05, FZI, Mainz)
• Prof. Thomas Kindler (University Cancer Center)
• Prof. Wilfried Roth (Institute of Pathology)
• Dr. Daniel Wagner (Institute of Pathology)
• Dr. Federico Marini (IMBEI)

National Partners

• Prof. Özlem Türeci (SFB 1292 TP22, HI-TRON, Mainz)
• Prof. Matthias Gaida (SFB 1292 TP22, TRON Mainz)
• Prof. Stefan Fröhling (National Center for Tumor Diseases, Heidelberg)
• Dr. Simon Kreutzfeld (National Center for Tumor Diseases, Heidelberg)

Research funding

• DFG (SFB 1292 TP10)
• HI-TRON (HITR-2021-10) (Project 3)

Biography - Claudine Graf

Team - Junior group Coagulation factors in immunity

Miscellaneous

We are looking forward to applications from highly motivated scientists per  Email.

Original articles

• Haist M, Stege H, Pemler S, Heinz J, Fleischer MI, Graf C, Ruf W, Loquai C, Grabbe S. Anticoagulation with factor Xa inhibitors is associated with improved overall response and progression-free survival in patients with metastatic malignant melanoma receiving immune checkpoint inhibitors – a retrospective, real-world cohort study. Cancers (Basel). 2021 Oct 2;13(20):5103.
• Graf C, Wilgenbus P, Pagel S, Pott J, Marini F, Reyda S, Kitano M, Macher-Göppinger S, Weiler H, Ruf W. Myeloid cell-synthesized coagulation factor X dampens antitumor immunity. Sci Immunol. 2019 Sep 20;4(39). pii: eaaw8405.
• Müller-Calleja N, Hollerbach A, Ritter S, Pedrosa DG, Strand D, Graf C, Reinhardt C, Strand S, Poncelet P, Griffin JH, Lackner KJ, Ruf W. Tissue factor pathway inhibitor primes monocytes for antiphospholipid antibody-induced thrombosis. Blood. 2019 Oct 3;134(14):1119-1131.
• Landtwing V, Raykova A, Pezzino G, Beziat V, Marcenaro E, Graf C, Moretta A, Capaul R, Zbinden A, Ferlazzo G, Malmberg KJ, Chijioke O, Munz C.  Cognate HLA absence in trans diminishes human NK cell education. J Clin Invest. 2016;126(10):3772-3782.
• Becker M*, Graf C*, Tonak M, Radsak MP, Bopp T, Bals R, Bohle RM, Theobald M, Rommens PM, Proschek D, Wehler TC Xenograft models for undifferentiated pleomorphic sarcoma not otherwise specified are essential for preclinical testing of therapeutic agents. Oncol Lett. 2016,12(2):1257-1264 3782.
• Allami RH*, Graf C*, Martchenko K, Voss B, Becker M, Berger MR, Galle PR, Theobald M, Wehler TC, Schimanski CC. Analysis of the expression of SDF-1 splicing variants in human colorectal cancer and normal mucosa tissues. Oncol Lett. 2016;11(3):1873-1878.
• Wehler TC, Martchenko K, Allami RH, Becker M, Wehler B, Berger MR, Bals R, Galle PR, Theobald M, Graf C*, Schimanski CC*. Functional diversity of stromal cell-derived factor 1 splice variants in colorectal cancer and melanoma. Int J Colorectal Dis. 2016;31(6):1225-6.
• Gur-Cohen S, Itkin T, Chakrabarty S, Graf C, Kollet O, Ludin A, Golan K, Kalinkovich A, Ledergor G, Wong E, Niemeyer E, Porat Z, Erez A, Sagi I, Esmon CT, Ruf W, Lapidot T. PAR1 signaling regulates the retention and recruitment of EPCR-expressing bone marrow hematopoietic stem cells. Nat Med. 2015;21(11):1307-17.

*shared authorship

Reviews

• Ruf W, Graf C. Coagulation signaling and cancer immunotherapy. Thromb Res. 2020 Jul;191 Suppl 1:S106-S111.
• Graf C, Ruf W. Tissue factor as a mediator of coagulation and signaling in cancer and chronic inflammation. Thromb Res. 2018;164 Suppl 1:S143-S147.
• Ruf W, Rothmeier AS, Graf C. Targeting clotting proteins in cancer therapy - progress and challenges. Thromb Res. 2016;140 Suppl 1:S1-7.
• Gur-Cohen S, Kollet O, Graf C, Esmon CT, Ruf W, Lapidot T. Regulation of long-term repopulating hematopoietic stem cells by EPCR/PAR1 signaling. Ann N Y Acad Sci. 12016;370(1):65-81.