Lectin-like transcript-1 (LLT1) and exosomal PCNA inhibit NK cell effector function against prostate cancer cells (TUM2P.892)

Abstract

NK cell functions are regulated by inhibitory and activating receptors binding corresponding ligands on the surface of target cells, providing vital first line defenses against infections and cancer. In order to establish and grow, cancer cells must escape NK cell-mediated killing. By altering the expression of ligands for NK cell receptors (down-regulating activating ligands and up-regulating inhibitory ligands) cancer cells may evade NK mediated killing. Here we have examined the expression of LLT1 (Lectin-like transcript-1 or CLEC2D), a ligand for the NK cell inhibitory receptor NKRP1A (CD161) as well as proliferating cell nuclear antigen (PCNA), a ligand for NKp44 on surface of prostate cancer cell DU145. Expression of LLT1 on DU145 cell inhibited NK cell cytolytic activity though NKRP1A (CD161). Similarly, expression of exosomal PCNA by DU145 inhibited NK cell cytotoxicity through NKp44. The association of HLA I and PCNA on DU145 forms an inhibitory ligand for NKp44. Blocking the inhibitory signals by anti-LLT1 and anti-NKp44 monoclonal antibodies enhanced the killing of prostate cancer cells by NK cells. Thus tumor cells may use multiple pathways to inhibit NK effector function and combinatorial targeting of these pathways could lead to efficient elimination of cancer cells.