Visual Universitätsmedizin Mainz

Junior group 'Coagulation factors in immunity'

PD Claudine Graf, MD PhD 

Group leader

The hemostatic system has evolved as an integral component of the innate immune defense against tissue injury. The cellular receptors for coagulation proteases are structurally related to interleukin, CD1d, and toll-like (TLR) receptors. The coagulation receptors tissue factor (TF) and the endothelial protein C receptor (EPCR) interact with coagulation factors FX and FVII and protein C (PC). TF can form two distinct complexes, either the binary TF/FVIIa or the ternary TF/FVIIa/FXa complex that utilize unique signal transduction mechanisms by proteolytically activating the G protein-coupled protease activated receptors (PARs). Activation of PAR2 in particular plays an important role in regulating toll-like receptor (TLR) signaling pathways. EPCR appears to support PAR2 cleavage by FXa on macrophages (MΦ) and dendritic cells (DCs). 

The junior group specifically focuses on defining cell type-specific roles of FX and FVII expressed by MΦ or DCs in tumor progression and cross-presentation, the latter being relevant for the induction of efficient anti-tumor T-cell immunity. F7flfl and F10flfl mice crossed with LysM-cre, CD11c-cre and CX3CR1-cre deleter lines will be used to characterize alterations in the tumor microenvironment (TME) but also in distant organs. We will further characterize the interaction of FVIIa- and FXa-signaling in MΦ or DCs with TLR and check point signaling in vivo and in vitro. We aim to understand how effects of FX relate to other regulatory signaling pathways involved in immune responses and how they can be potentially targeted by existing anticoagulants or checkpoint inhibitors, which would be very attractive for clinical practice.

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

  • Prof. Thomas Wölfel (III. Medical Department)
  • PD. Heidi Rossmann (Laboratory Medicine / CTH)
  • Prof. Wolfram Ruf, Dr. Sebastian Schubert (CTH)
  • PD Dr. Niels Lemmermann, Prof. Matthias Reddehase (Virology)
  • Prof. Ugur Sahin (TRON)
  • Prof. Christian Münz (Zürich)
  • Prof. Benoit van den Eynde, Prof. Pierre van der Bruggen (Ludwig Cancer Research, Brussel)

Research funding

  • BMBF (CTH, 01EO1503)
  • DFG (SFB 1292)

Team - Junior group Coagulation factors in immunity

Platzhalterbild
PD Claudine Graf, MD PhD
Position: Junior group leader
Physician Outpatient Clinic
Qualifications: Specialist in Internal Medicine, Hematology and Oncology, Additional qualification: Palliative Care, Hemostaseology

06131 17-8014 (Office) bzw. -8027 (Lab)
grafc@uni-mainz.de

Platzhalterbild
Petra Wilgenbus
Position: Technician

06131 17-8028
wilgenbu@uni-mainz.de

Original articles

  • Myeloid cell-synthesized coagulation factor X dampens antitumor immunity. Graf C, Wilgenbus P, Pagel S, Pott J, Marini F, Reyda S, Kitano M, Macher-Göppinger S, Weiler H, Ruf W. Sci Immunol. 2019 Sep 20;4(39). pii: eaaw8405. doi: 10.1126/sciimmunol.aaw8405.
  • Tissue factor pathway inhibitor primes monocytes for antiphospholipid antibody-induced thrombosis. 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. Blood. 2019. pii: blood.2019001530. [Epub ahead of print]
  • 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

  • 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