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

• 成果类型: Article
• 署名作者: Deng, Zihou; Loyher, Pierre-Louis; Lazarov, Tomi; Li, Li; Shen, Zeyang; Bhinder, Bhavneet; Yang, Hairu; Zhong, Yi; Alberdi, Araitz; Massague, Joan; Sun, Joseph C.; Benezra, Robert; Glass, Christopher K.; Elemento, Olivier; Iacobuzio-Donahue, Christine A.; Geissmann, Frederic
• 署名单位: Memorial Sloan Kettering Cancer Center; Cornell University; City University of New York (CUNY) System; University of California System; University of California San Diego; University of California System; University of California San Diego; Cornell University; Weill Cornell Medicine; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5612
• DOI: 10.1038/s41586-023-06950-4
• 发表日期: 2024-02-22
• 关键词: loop-helix proteins; circulating tumor-cells; kupffer cells; apoptotic cells; mutant p53; stem-cells; GROWTH; differentiation; phagocytosis; induction

摘要

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. The Kupffer cell lineage-determining factor ID3 selectively endows macrophages with the ability to phagocytose live tumour cells and orchestrate the recruitment, proliferation and activation of natural killer and CD8+ T lymphoid effector cells to restrict the growth of a variety of tumours.