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

Zihou Deng, Pierre-Louis Loyher, Tomi Lazarov, Li Li, Zeyang Shen, Bhavneet Bhinder, Hairu Yang, Yi Zhong, Araitz Alberdi, Joan Massague, Joseph C. Sun, Robert Benezra, Christopher K. Glass, Olivier Elemento, Christine A. Iacobuzio-Donahue and Frederic Geissmann ()
Additional contact information
Zihou Deng: Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
Pierre-Louis Loyher: Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
Tomi Lazarov: Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
Li Li: City University of New York
Zeyang Shen: University of California, San Diego
Bhavneet Bhinder: Institute for Computational Biomedicine, Weill Cornell
Hairu Yang: Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
Yi Zhong: Memorial Sloan Kettering Cancer Center
Araitz Alberdi: Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
Joan Massague: Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
Joseph C. Sun: Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
Robert Benezra: Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
Christopher K. Glass: University of California, San Diego
Olivier Elemento: Institute for Computational Biomedicine, Weill Cornell
Christine A. Iacobuzio-Donahue: Memorial Sloan Kettering Cancer Center
Frederic Geissmann: Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center

Nature, 2024, vol. 626, issue 8000, 864-873

Abstract: Abstract Macrophage activation is controlled by a balance between activating and inhibitory receptors1–7, which protect normal tissues from excessive damage during infection8,9 but promote tumour growth and metastasis in cancer7,10. Here we report that the Kupffer cell lineage-determining factor ID3 controls this balance and selectively endows Kupffer cells with the ability to phagocytose live tumour cells and orchestrate the recruitment, proliferation and activation of natural killer and CD8 T lymphoid effector cells in the liver to restrict the growth of a variety of tumours. ID3 shifts the macrophage inhibitory/activating receptor balance to promote the phagocytic and lymphoid response, at least in part by buffering the binding of the transcription factors ELK1 and E2A at the SIRPA locus. Furthermore, loss- and gain-of-function experiments demonstrate that ID3 is sufficient to confer this potent anti-tumour activity to mouse bone-marrow-derived macrophages and human induced pluripotent stem-cell-derived macrophages. Expression of ID3 is therefore necessary and sufficient to endow macrophages with the ability to form an efficient anti-tumour niche, which could be harnessed for cell therapy in cancer.

Date: 2024
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DOI: 10.1038/s41586-023-06950-4

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