SIRPα controls CD47-dependent platelet clearance in mice and humans

Maia Shoham; Ying Ying Yiu; Paige S Hansen; Aanya Subramaniam; Martin Broberg; Eric Gars; Tal Raveh; FinnGen; Irving L Weissman; Nasa Sinnott-Armstrong; Anandi Krishnan; Hanna M Ollila; Michal Caspi Tal

doi:10.1101/2023.12.09.570874

SIRPα controls CD47-dependent platelet clearance in mice and humans

bioRxiv [Preprint]. 2023 Dec 10:2023.12.09.570874. doi: 10.1101/2023.12.09.570874.

Authors

Maia Shoham^{1

2}, Ying Ying Yiu^{1

2}, Paige S Hansen^{1

3}, Aanya Subramaniam³, Martin Broberg⁴, Eric Gars⁵, Tal Raveh¹, FinnGen^{1

2

4

5

6

7

8

9

10

11

12

3}, Irving L Weissman^{1

2}, Nasa Sinnott-Armstrong^{6

7}, Anandi Krishnan^{5

9}, Hanna M Ollila^{4

10

11

12}, Michal Caspi Tal^{1

3}

Affiliations

¹ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
² Ludwig Cancer Center, Stanford University School of Medicine, Stanford, CA, USA.
³ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁴ Institute for Molecular Medicine, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland.
⁵ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
⁶ Department of Genetics, Stanford University, Stanford, CA, USA.
⁷ Metabolism Program and Cardiovascular Disease Initiative, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.
⁸ Herbold Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, USA.
⁹ Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
¹⁰ Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹¹ Broad Institute for Harvard and MIT, Boston, MA, USA.
¹² Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Abstract

Over the last decade, more data has revealed that increased surface expression of the "don't eat me" CD47 protein on cancer cells plays a role in immune evasion and tumor progression, with CD47 blockade emerging as a new therapy in immuno-oncology. CD47 is critical in regulating cell homeostasis and clearance, as binding of CD47 to the inhibitory receptor SIRPα can prevent phagocytosis and macrophage-mediated cell clearance. The purpose of this study was to examine the role of the CD47-SIRPα signal in platelet homeostasis and clearance. Therapeutic reagents targeting the CD47-SIRPα axis are very promising for treatment of hematologic malignancies and solid tumors, but lead to transient anemia or thrombocytopenia in a subset of patients. We found that platelet homeostatic clearance is regulated through the CD47-SIRPα axis and that therapeutic blockade to disrupt this interaction in mice and in humans has a significant impact on platelet levels. Furthermore, we identified genetic variations at the SIRPA locus that impact platelet levels in humans such that higher SIRPA gene expression is associated with higher platelet levels. SIRPA expression at either end of the normal range may affect clinical outcomes of treatment with anti-CD47 therapy.

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Preprint

Abstract

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