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The nuclear factor ID3 endows macrophages with a potent anti-tumor activity

ABSTRACT: Macrophage activation is controlled by a balance between activating and inhibitory receptors which protect normal tissues from excessive damage during infection but promote tumor growth and metastasis in cancer. We report here that the Kupffer cell (KC)-lineage determining factor ID3 controls this balance and selectively endows KC with the ability to phagocytose live tumor cells and orchestrate the recruitment, proliferation, and activation of NK and CD8 T lymphoid effector cells in the liver to restrict the growth of a variety of tumors. ID3 shifts the macrophage inhibitory/activating receptor balance to unleash the phagocytic and lymphoid response, at least in part by buffering binding of the transcription factors ELK1 and E2A at the Sirpα locus. Furthermore, loss- and gain-of-function experiments demonstrate that ID3 is sufficient to confer this potent anti-tumor activity to mouse bone marrow derived macrophages and human induced pluripotent stem cells derived macrophages. Expression of ID3 is therefore necessary and sufficient to endow macrophages with the ability to form an efficient anti-tumor niche, which could be harnessed for cell therapy in cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE234638 | GEO | 2023/11/14

REPOSITORIES: GEO

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The Kupffer cell-specifying factor Id3 endows macrophages with antimetastatic activity

Project description:The anti-tumor activity of macrophages is mediated in part via phagocytosis and controlled by a balance between the recognition of live cells by activating receptors and inhibitory receptors. The latter protects host tissues during infection but allows tumoral cells to escape phagocytosis and promotes metastasis. We investigated the mechanisms that control anti-metastatic activity of macrophages and found that the transcriptional repressor and Kupffer cells (KC)-specifying factor ID3 is required and sufficient to orchestrate tumor cell killing by macrophages in vivo and in vitro and reduces by ~50% liver and lung colonization by metastatic-initiating cells invading from the portal vein in long-term orthotopic pancreatic cancer models. Loss-of-function and gain -of functions experiments indicate that ID3 controls expression of activating and inhibitory receptors, in particular the inhibitory receptor SIRPα, which boost their phagocytic activity against tumor cells. Mechanistically, ID3 prevents binding of ELK1 and the E-Box factor E2A to promoter/enhancer regions of the inhibitory receptor Sirpα gene, which limits expression of SIRPα at levels compatible with efficient phagocytosis of tumor cells and prevents its upregulation by inflammatory stimuli. This mechanism endows macrophages with anti-metastatic activity.

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