GSE186082
Circulating tumor cell-derived N-cadherin induces NK cell exhaustion and contributes to tumor self-seeding via the KLRG1 receptor
Circulating tumor cells (CTCs) can survive in the circulation and return to primary tumors through a self-seeding process. However, the mechanisms underlying CTC escape from natural killer (NK) cell-mediated immune surveillance remain unclear. In the present study, self-seeded tumor cells were isolated and characterized by applying a modified mouse model. The harvested self-seeded cells displayed resistance to NK cell-mediated lysis and a higher tumor seeding ability than their parental cells. Elevated expression levels of the CDH2 gene and its protein product, N-cadherin were found in self-seeded cell lines. We revealed an unrecognized role for soluble N-cadherin in inhibiting NK cell antitumor immunity. NK cells secreted cytokines, and fluid shear stress facilitated N-cadherin release from tumor cells by enhancing the activity of A disintegrin and metalloprotease 10 (ADAM10). Soluble N-cadherin triggered NK cell functional exhaustion by interacting with the killer cell lectin-like receptor subfamily G member 1 (KLRG1) receptor and therefore protected tumor cells from NK cell killing. Elevated N-cadherin expression was observed in recurrent oral cancer samples compared to matched primary tumors. Our findings illustrated an unknown mechanism by which CTCs evaded NK cell-mediated immune surveillance, which may contribute to tumor self-seeding and recurrence. Overall design: Examination of differentially expressed mRNAs between SCC9-seeded and SCC9-parental cells.