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

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

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.

• Journal Article Type: Article
• Acceptance Date: Mar 18, 2024
• Online Publication Date: Mar 20, 2024
• Publication Date: Apr 19, 2024
• Deposit Date: Mar 25, 2024
• Publicly Available Date: Mar 26, 2024
• Journal: iScience
• Electronic ISSN: 2589-0042
• Publisher: Cell Press
• Peer Reviewed: Peer Reviewed
• Volume: 27
• Issue: 4
• Article Number: 109546
• DOI: https://doi.org/10.1016/j.isci.2024.109546
• Keywords: Molecular biology; Immunology; Cell biology; Stem cells research; Cancer
• Public URL: https://nottingham-repository.worktribe.com/output/33015419
• Additional Information: This article is maintained by: Elsevier; Article Title: Disruption of CD47-SIRPα signalling restores inflammatory function in tumour-associated myeloid derived suppressor cells; Journal Title: iScience; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.isci.2024.109546; Content Type: article; Copyright: © 2024 The Authors. Published by Elsevier Inc.