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The nuclear factor ID3 endows macrophages with a potent anti-tumour activity
Nature ( IF 50.5 ) Pub Date : 2024-02-07 , DOI: 10.1038/s41586-023-06950-4
Zihou Deng 1 , Pierre-Louis Loyher 1 , Tomi Lazarov 1, 2 , Li Li 3 , Zeyang Shen 4, 5 , Bhavneet Bhinder 6 , Hairu Yang 1 , Yi Zhong 7 , Araitz Alberdi 1 , Joan Massague 8 , Joseph C Sun 1 , Robert Benezra 8 , Christopher K Glass 4 , Olivier Elemento 6 , Christine A Iacobuzio-Donahue 7 , Frederic Geissmann 1, 2
Affiliation  

Macrophage activation is controlled by a balance between activating and inhibitory receptors1,2,3,4,5,6,7, 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.



中文翻译:


核因子ID3赋予巨噬细胞强大的抗肿瘤活性



巨噬细胞的激活由激活受体和抑制受体之间的平衡控制1,2,3,4,5,6,7 ,它可以保护正常组织在感染过程中免受过度损伤8,9 ,但会促进癌症中的肿瘤生长和转移7,10 。在这里,我们报告说,库普弗细胞谱系决定因子ID3控制着这种平衡,并选择性地赋予库普弗细胞吞噬活肿瘤细胞的能力,并协调肝脏中自然杀伤细胞和 CD8 T 淋巴细胞效应细胞的招募、增殖和激活,以限制各种肿瘤的生长。 ID3 至少部分通过缓冲SIRPA位点转录因子 ELK1 和 E2A 的结合来改变巨噬细胞抑制/激活受体平衡,以促进吞噬和淋巴反应。此外,功能丧失和获得的实验表明,ID3 足以赋予小鼠骨髓来源的巨噬细胞和人类诱导的多能干细胞来源的巨噬细胞这种有效的抗肿瘤活性。因此,ID3 的表达对于赋予巨噬细胞形成有效的抗肿瘤生态位的能力是必要且充分的,可用于癌症的细胞治疗。

更新日期:2024-02-09
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