LAIR1 suppresses phagocytosis via SHP2/USP22-mediated MYH9 degradation in glioma-associated microglia/macrophages to drive immunosuppression
Menée à l'aide d'une lignée cellulaire, d'un modèle murin, de macrophages issus de moelle osseuse et de macrophages ou microglie associés à des gliomes d'origine humaine, cette étude met en évidence un mécanisme par lequel le récepteur LAIR1 favorise l'immunosuppression en supprimant la phagocytose via la déphosphorylation de la protéine MYH9 au niveau de la sérine 1943, l'inhibition du recrutement de la peptidase USP22 ainsi que le blocage de la déubiquitination et de la stabilisation de MYH9 et du facteur HIF1alpha
Background : Glioma immunotherapy faces major challenges due to the pervasive presence of glioma-associated microglia/macrophages (GAMs) and inadequate T-cell responses. LAIR1 is highly expressed in GAMs and correlates with poor glioma prognosis. This study investigated its role in GAMs and immunosuppression in glioma.
Methods : LAIR1 expression was analysed via bioinformatics, flow cytometry, and multiplex immunohistochemical staining. Its function was studied using Lair1
−
/
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mice, engineered BV2 cells, bone marrow-derived macrophages (BMDMs), patient-derived GAMs, and techniques including RNA-seq, PCR array, co-immunoprecipitation, molecular dynamics analysis, and CRISPR/Cas9.
Results : LAIR1 was predominantly expressed on GAMs, and high infiltration of LAIR1high GAMs correlated with poor patient survival. In orthotopic glioma models, LAIR1 deficiency reduced tumour burden. LAIR1high GAMs exhibited an immunosuppressive phenotype, associated with the CD47-SIRPA axis. These GAMs conferred resistance to anti-PD-1 therapy. LAIR1 deficiency enhanced GAM tumoricidal activity in vitro. Mechanistically, collagen I-activated LAIR1 promoted SHP2-dependent dephosphorylation of MYH9 at Ser1943. This inhibited USP22 recruitment, blocking USP22-mediated deubiquitylation and stabilisation of MYH9 and HIF1
α, ultimately suppressing GAM phagocytosis.
Conclusion
:
LAIR1 is a critical phagocytosis suppressor in GAMs, driving glioma immunosuppression. Targeting LAIR1 represents a promising strategy to restore anti-tumour immunity.
British Journal of Cancer , résumé, 2026