Reinvigorating COTL1high NK cells via GITR signalling overcomes immune checkpoint blockade resistance in tsMHC-I-impaired tumours - PubMed
8 hours ago
- #GITR signaling
- #COTL1high NK cells
- #tsMHC-I-impaired tumours
- Patients with impaired tumour-specific MHC class I (tsMHC-I) often resist immune checkpoint blockade (ICB), but some remain responsive.
- A subset of COTL1high natural killer (NK) cells is identified as key to ICB responsiveness in these patients.
- PD-L1+ macrophages express GITRL, engaging GITR on COTL1high NK cells; anti-PD-L1 relieves PD-1-mediated inhibition of GITR signaling.
- Activation of COTL1high NK cells via GITR enhances immunological synapse stability and IFN-γ production through a metabolic-H3K27ac-RBPJ axis.
- This activation upregulates tsMHC-I expression, boosting adaptive anti-tumour immunity.
- GITR activation improves anti-PD-L1 therapy sensitivity in tsMHC-I-impaired models, suggesting GITRL-GITR axis as a therapeutic target.