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Circulating tumor cell-derived N-cadherin induces NK cell exhaustion and contributes to tumor self-seeding via the KLRG1 receptor

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE186082 | GEO | 2022/09/21

REPOSITORIES: GEO

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Project description:Tumor cells dissociate from the primary site and enter into systemic circulation (circulating tu-mor cells, CTCs) either alone or Tumor cells dissociate from the primary site and enter into systemic circulation (circulating tu-mor cells, CTCs) either alone or as tumor microemboli (clusters); the latter having an increased predisposition towards forming distal metastases than single CTCs. The formation of clusters is, in part, created by contacts between cell–cell junction proteins and/or cytokine receptor pairs with other cells such as neutrophils, platelets, fibroblasts, etc. In the present study, we provide evidence for an extravesicular (EV) mode of communication between pancreatic cancer CTCs and neutrophils. Our results suggest that the EV proteome of CTCs contain signaling proteins that can modulate degranulation and granule mobilization in neutrophils and, also, contain tis-sue plasminogen activator and other proteins that can regulate cluster formation. By exposing naïve neutrophils to EVs isolated from CTCs, we further show how these changes are modulated in a dynamic fashion indicating evidence for a deeper EV based remodulatory effect on com-panion cells in clusters.as tumor microemboli (clusters); the latter having an increased predisposition towards forming distal metastases than single CTCs. The formation of clusters is, in part, created by contacts between cell–cell junction proteins and/or cytokine receptor pairs with other cells such as neutrophils, platelets, fibroblasts, etc. In the present study, we provide evidence for an extravesicular (EV) mode of communication between pancreatic cancer CTCs and neutrophils. Our results suggest that the EV proteome of CTCs contain signaling proteins that can modulate degranulation and granule mobilization in neutrophils and, also, contain tis-sue plasminogen activator and other proteins that can regulate cluster formation. By exposing naïve neutrophils to EVs isolated from CTCs, we further show how these changes are modulated in a dynamic fashion indicating evidence for a deeper EV based remodulatory effect on com-panion cells in clusters.

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Circulating tumor cell-derived N-cadherin induces NK cell exhaustion and contributes to tumor self-seeding via the KLRG1 receptor

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