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

Nature · 16 authors, 8 centres

AI SUMMARY

FIDELITY 100%

This summary was generated by AI from a single paper. It has not been reviewed by a clinician and is not clinical advice. Verify against the source before acting on it.

AGENT 01 · STRUCTURED SUMMARY

TRACE TO SOURCE

“

TL;DR

This preclinical study used mouse models and iPSC-derived macrophages to show that the transcription factor ID3, expressed in liver-resident Kupffer cells, controls the balance between inhibitory and activating receptors on macrophages, enabling them to phagocytose tumour cells and recruit anti-tumour lymphocytes.

Full summary

541 CHARS

ID3 was found to directly repress the inhibitory receptor Sirpa by inhibiting binding of transcription factors E2A and ELK1 to Sirpa promoter and enhancer regions. Low Sirpa expression enabled KC activation by CD47-expressing cancer cells, at least in part through the activating receptor dectin-1, resulting in phagocytosis of live tumour cells and production of chemokines that recruited NK cells and CD8+ T cells. Enforced ID3 expression in other macrophage types, including human iPSC-Macs, was sufficient to confer anti-tumour activity.

STUDY TYPE

other

SPECIALTY

oncology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10881399

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

Nature

READ THE FULL PAPER

ABSTRACT

Abstract Macrophage activation is controlled by a balance between activating and inhibitory receptors 1 – 7 , which protect normal tissues from excessive damage during infection 8 , 9 but promote tumour growth and metastasis in cancer 7 , 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. Subject terms: Tumour immunology, Tumour immunology

CITATION EXPORT

Zihou Deng, Pierre-Louis Loyher, Tomi Lazarov et al.. The nuclear factor ID3 endows macrophages with a potent anti-tumour activity. Nature. (2024). https://doi.org/10.1038/s41586-023-06950-4

AUTHORS

16 · 8 CENTRES

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, Frederic Geissmann

1Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY USA
2Weill Cornell Graduate School of Medical Sciences, New York, NY USA
3Graduate Center, City University of New York, New York, NY USA
4Department of Bioengineering, University of California, San Diego, La Jolla, CA USA
5Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA USA
6Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell, New York, NY USA
7Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY USA
8Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY USA