OC 12.1 - Unraveling CD200R1 as a novel mechanism of thromboinflammation in cancer

Sunday, June 23, 2024

09:30 – 09:45 ICT

Room: Ballroom B2

Presenting Author(s)

MB

Marisa A. Brake, PhD

Postdoctoral Fellow
Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center and Harvard Medical School
Boston, Massachusetts, United States

Co-Author(s)

DK

Dimitra Karagkouni

Postdoctoral Fellow
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States
Rushad Patell, MBBS

Assistant Professor
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States
JL

Jacob G. Ludington

Research Fellow in Medicine
Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center and Harvard Medical School
Boston, Massachusetts, United States
Anna Falanga, MD PhD

MD, PhD, Prof
University of Milano Bicocca, School of Medicine, Monza, Italy
Bergamo, Lombardia, Italy
Marina Marchetti

MSc, PhD
Division of Immunohematology and Transfusion Medicine, Hospital Papa Giovanni XXIII,Bergamo
Bergamo, Lombardia, Italy
LR

Laura Russo

MSc
Division of Immunohematology and Transfusion Medicine, Hospital Papa Giovanni XXIII, Bergamo, Italy
Bergamo, Lombardia, Italy
Simon Mantha

Attending Physician
Hematology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
New York, New York, United States
Marc Carrier, MD

Professor
Department of Medicine, University of Ottawa at the The Ottawa Hospital
Ottawa, Ontario, Canada
PW

Phil S. Wells

Chair and Chief, Department of Medicine
University of Ottawa
Ottawa, Ontario, Canada
DN

Donna Neuberg

Senior Lecturer
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
Robert Flaumenhaft, MD, PhD

Professor
BIDMC/Harvard Medical School
Boston, Massachusetts, United States
IV

Ioannis Vlachos

Co-Director of the Bioinformatics Program, Cancer Research Institute
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States
Jeffrey I. Zwicker, MD

Chief of Hematology Service
Hematology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
New York, New York, United States
Sol Schulman, MD, PhD

Assistant Professor of Medicine
Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center and Harvard Medical School
Boston, Massachusetts, United States

Background: We performed proteomics to identify novel biomarkers predictive of cancer-associated thrombosis. We identified that low levels of CD200R1, an inhibitory receptor limiting leukocyte inflammatory response, predict development of thrombosis. CD200R1 has not previously been linked with a prothrombotic state.

Aims: To investigate the mechanism by which reduced CD200R1 promotes thrombosis.

Methods: Plasma was isolated from ~8-week Cd200r1-/- or wildtype mice. Coagulation times and factor levels were determined by coagulometry. Thrombin-antithrombin complexes (TAT), TF, TFPI, soluble thrombomodulin, IL-17a, ICAM-1, E-Selectin, and P-Selectin were determined by ELISA. Extracellular vesicles were counted by nanoparticle tracking. Proximity extension and aptamer-based proteomics were deployed in mouse and human plasma, respectively.

Results: TAT was significantly increased in Cd200r1-/- mice (p < 0.01), indicating enhanced thrombin generation in vivo. No differences were observed in plasma factor V, VII, VIIa, X, prothrombin, or fibrinogen. Similarly, no differences were observed in plasma TF, TFPI, thrombomodulin, or circulating extracellular vesicle count, and RNA sequencing of mouse liver did not identify significant gene expression changes in coagulation factors. We therefore used proteomics to evaluate relative plasma protein abundance in Cd200r1-/- mice as compared to control, and the most significant alteration was elevated IL-17a (q=6x10-5) which was confirmed by ELISA (p < 0.01). IL-17a is implicated in cardiovascular disease through endothelial activation. We noted increased endothelial markers including TGFBR3 (q=0.01), ICAM-1 (p < 0.01), E-Selectin (p < 0.01), and P-Selectin (p < 0.05) in Cd200r1-/- mice. We evaluated the CD200R1/IL-17a axis in patients with cancer. Lower levels of CD200R1 were associated with higher IL-17a levels (p < 0.05) while IL-17a levels were significantly increased in cancer patients who developed thrombosis (p=0.01).

Conclusion(s): Decreased CD200R1 leads to aberrant production of IL-17a to promote endothelial inflammation and thrombin generation in vivo without altered levels of coagulation proteins. Therapeutic targeting of the CD200R1/IL-17a axis may represent a novel strategy to manage thromboinflammation, including cancer-associated thrombosis.