N-cadherin protects oral cancer cells from NK cell killing in the circulation by inducing NK cell functional exhaustion via the KLRG1 receptor

Background: Circulating tumor cells (CTCs) can survive in the circulation and return to primary tumors through a self-seeding process. However, the mechanisms underlying CTCs escape from natural killer (NK) cell-mediated immune surveillance remain unclear.

Method: Self-seeded tumor cells were isolated and characterized using a modified contralateral seeding model. A comparison of transcriptional profiles was performed between the parental cells and self-seeded cells. The molecular mechanism of self-seeded tumor cells escaping from NK cell was demonstrated through in vitro experiments and verified in a CTC-mimicking in vivo model. Then, the expression level of key protein mediating CTCs immune escape was detected in 24 paired primary and recurrent tumor samples of patients with oral cancer by the immunohistochemical method.

Result: 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 cells. NK cells secreted cytokines, and fluid shear stress facilitated N-cadherin release by promoting A disintegrin and metalloprotease 10 (ADAM10) translation or converting the precursor ADAM10 to the mature form. 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 in the circulation. In vivo experimental results showed that overexpression of N-cadherin promoted tumor self-seeding and facilitated the survival of CTCs. Compared with primary tumors, N-cadherin expression was significantly increased in matched recurrent tumor tissues.

Conclusion: Together, our findings illustrate an unknown mechanism by which CTCs evaded NK cell-mediated immune surveillance, and indicate that targeting N-cadherin is an effective strategy to prevent CTCs from homing to primary tumor.