抗 PD-1 治疗通过 PVR/TIGIT 通路逆转肝细胞癌免疫治疗耐药中 TIGIT(+)CD226(+)NK 的耗竭

Immunotherapy resistance conducts the main reason for failure of PD-1-based immune checkpoint inhibitors (ICIs) in patients with hepatocellular carcinoma (HCC).

This study aims to clarify the mechanism of nature kill cells (NK) depletion in immunotherapy resistance of HCC. Cancerous /paracancerous tissues and peripheral blood (PB) of 55 HCC patients were collected and grouped according to differentiation degree, FCM, IHC and lymphocyte culture drug intervention experiments were used to determine NK cell depletion degree.

Furthermore, a mouse model of HCC in situ was constructed and divided into different groups according to intervention measures of ICIs. Immunofluorescence thermography was used to observe changes in tumor burden. NK cells in cancerous tissues significantly up-regulated TIGIT expression (P < 0. 001).

Intervention experiments revealed that TIGIT and PD-1 expression decreased gradually with increased PD-1 inhibitor dose in moderately-highly differentiated patients (P < 0. 05). Animal experiment showed that tumors proliferation in experimental group was inhibited after PD-1 blockage, WB indicated that ICIs decreased TIGIT and PVRL1 protein expression while increased CD226 and PVRL3 protein expression.

We concluded that TIGIT + NK cells competitively bind to PVR with CD226 and promote NK cell depletion. Anti-PD-1 decreases PVRL1 expression through PD-1/PD-L1 pathway, reducing the PVR/TIGIT inhibitory signal pathway, and enhancing function of PVR/CD226 activation signal.