Journal Article

DKFZ-2024-00683

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Disruption of CD47-SIRPα signaling restores inflammatory function in tumor-associated myeloid-derived suppressor cells.

Zimarino, C. ; Moody, W. ; Davidson, S. E. ; Munir, H.DKFZ* ; Shields, J. D.

2024
Elsevier St. Louis

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Please use a persistent id in citations: doi:10.1016/j.isci.2024.109546

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.

Keyword(s): Cancer ; Cell biology ; Immunology ; Molecular biology ; Stem cells research

Note: HI-TRON

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Contributing Institute(s):

1. NWG Dermale Onkoimmulologie (D195)

Research Program(s):

1. 314 - Immunologie und Krebs (POF4-314) (POF4-314)

Appears in the scientific report 2024

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