Disruption of CD47-SIRPα signaling restores inflammatory function in tumor-associated myeloid-derived suppressor cells

Carlo Zimarino; William Moody; Sarah E Davidson; Hafsa Munir; Jacqueline D Shields

doi:10.1016/j.isci.2024.109546

Disruption of CD47-SIRPα signaling restores inflammatory function in tumor-associated myeloid-derived suppressor cells

iScience. 2024 Mar 20;27(4):109546. doi: 10.1016/j.isci.2024.109546. eCollection 2024 Apr 19.

Authors

Carlo Zimarino¹, William Moody¹, Sarah E Davidson^{1

2}, Hafsa Munir^{1

3

4}, Jacqueline D Shields^{1

5

6}

Affiliations

¹ MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK.
² The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
³ Helmholtz Institute for Translational Oncology Mainz (HI-TRON Mainz) - A Helmholtz Institute of the DKFZ, Mainz, Germany.
⁴ German Cancer Research Centre (DKFZ), Division of Dermal Oncoimmunology, Heidelberg, Germany.
⁵ Comprehensive Cancer Centre, Kings College London, London, UK.
⁶ Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK.

Abstract

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous immune population with diverse immunosuppressive functions in solid tumors. Here, we explored the role of the tumor microenvironment in regulating MDSC differentiation and immunosuppressive properties via signal-regulatory protein alpha (SIRPα)/CD47 signaling. In a murine melanoma model, we observed progressive increases in monocytic MDSCs and monocyte-derived dendritic cells that exhibited potent T cell-suppressive capabilities. These adaptations could be recapitulated in vitro by exposing hematopoietic stem cells to tumor-derived factors. Engagement of CD47 with SIRPα on myeloid cells reduced their phagocytic capability, enhanced expression of immune checkpoints, increased reactive oxygen species production, and suppressed T cell proliferation. Perturbation of SIRPα signaling restored phagocytosis and antigen presentation by MDSCs, which was accompanied by renewed T cell activity and delayed tumor growth in multiple solid cancers. These data highlight that therapeutically targeting myeloid functions in combination with immune checkpoint inhibitors could enhance anti-tumor immunity.

Keywords: Cancer; Cell biology; Immunology; Molecular biology; Stem cells research.