Laminin γ2-ITGβ1-PD-L1 axis mediates gastric cancer cell heterogeneity in response to GCMSCs via FAK/YAP pathway

Despite previous studies indicating that gastric cancer mesenchymal stromal cells (GCMSCs) raise PD-L1 levels in gastric cancer (GC) cells, the mechanisms underlying the heterogeneous responses of PD-L1^Low and PD-L1^High cell subpopulations to GCMSCs remain unclear.

Flow cytometry was employed to categorize GC cells into PD-L1^Low and PD-L1^High groups and mRNA sequencing was performed. Several experiments including western blotting, qRT-PCR, immunofluorescence, sphere formation assay and in vivo studies were performed to investigate the function of signaling pathway activation in GC progression.

Our findings demonstrated that the heterogeneous PD-L1 expression correlates with the gene signature of the Hippo pathway. The ITGβ1 expression in GC cells had a significant impact on PD-L1 responsiveness to GCMSCs. Mechanistically, FAK activation promoted PD-L1 upregulation by facilitating YAP nuclear accumulation. Furthermore, the interaction between ITGβ1 and Laminin γ2, which is derived from GCMSCs, upregulates the PD-L1 level and increases the stem-like properties of GC cells through the FAK/YAP pathway. Exploratory clinical analyses showed activation of the Laminin γ2 / ITGβ1 / PD-L1 axis and suggested an association with unfavorable clinical outcomes.