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MHC class I-LILRB3 delivers a punch to eliminate precancerous cells

Cellular & Molecular Immunology volume 19, pages 655–656 (2022)Cite this article

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In the study by Ayukawa et al. [1], the authors presented an innate defense mechanism whereby normal epithelial cells actively remove precancerous cells from the epithelium via mechanical extrusion (Fig. 1).

What are the mechanisms that keep normal cells harboring driver mutations in check? Increasingly, it is recognized that the surrounding microenvironment plays a pivotal role in determining the fate of mutant normal cells. Our body could elicit an immune response against nontransformed cells bearing neoantigens arising from genetic mutations [5]. In addition, epithelial cells possess an intrinsic defense mechanism known as an epithelial defense against cancer, which actively eliminates precancerous cells from the epithelial layer through cell competition. To study this phenomenon, Ayukawa et al. cocultured epithelial cells with isogenic counterparts with conditional RasG12V expression. Using an in vitro competition assay, they demonstrated that cells expressing RasG12V were actively extruded to the apical side of the monolayer. In wild-type cells cocultured with RasG12V cells, RUNX2 was upregulated in response to mechanical stress, as was its transcriptional target, LILRB3. Depletion of RUNX2 or LILRB3 in wild-type cells significantly impaired the apical extrusion of RasG12V cells, underscoring their roles in sensing transformed cells. LILRB3 is a member of the leukocyte immunoglobulin-like receptor (LIR) family and is known to interact with MHC class I molecules. Indeed, RasG12V expression induced MHC class I (HLA-B), and triple deletion of HLA genes in RasG12V cells reduced apical extrusion, implying an underlying role of the ILIRB3-MHC class I interaction in this process. Further mechanistic studies demonstrated that the LILRB3 D1 domain in wild-type cells directly interacts with the MHC α3 domain expressed on RasG12V cells in an intercellular fashion, which activates a SHP2-Rho-ROCK2 signaling pathway and culminates in apical extrusion via filamin accumulation.

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Fig. 1

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Acknowledgements

This project was supported by funding from the Research Grants Council-General Research Fund (24100520, 14108718, 14101321), Research Grants Council-Collaborative Research Fund (C4039-19G), and Heath and Medical Research Fund (06170686, 08190706).

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  1. Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China

    Chi Chun Wong & Jun Yu

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  1. Chi Chun Wong
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CCW and JY drafted and revised the paper.

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Correspondence to Chi Chun Wong or Jun Yu.

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Wong, C.C., Yu, J. MHC class I-LILRB3 delivers a punch to eliminate precancerous cells. Cell Mol Immunol 19, 655–656 (2022). https://doi.org/10.1038/s41423-021-00821-6

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