通过 GITR 信号重新激活 COTL1(high) NK 细胞可克服 tsMHC-I 受损肿瘤的免疫检查点阻断耐药

Patients with impaired tumour-specific major histocompatibility complex class I (tsMHC-I impaired ) often fail to respond to immune checkpoint blockade (ICB), presenting a major clinical challenge.

However, through our multicentre investigation, we observed that a subset of patients with tsMHC-I impaired remains responsive to ICB, a phenomenon that has not been fully explained.

Here we identify a COTL1 high natural killer (NK) subset that mediates ICB responsiveness in these patients.

Mechanistically, PD-L1 + macrophages coexpress GITRL and engage GITR on COTL1 high NK cells, whereas PD-L1 blockade relieves the PD-1-mediated inhibition of GITR signalling and promotes NK cell activation. Activated COTL1 high NK cells enhance immunological synapse stability and IFN-γ production via a metabolic-H3K27ac-RBPJ axis, thereby upregulating tsMHC-I expression and reinforcing adaptive anti-tumour immunity.

Notably, GITR activation significantly enhances the sensitivity to anti-PD-L1 therapy in tsMHC-I impaired models.

Our findings identify COTL1 high NK cells as key determinants of ICB responsiveness and highlight the GITRL-GITR axis as a promising therapeutic target for tsMHC-I impaired tumours.