Overexpression of LLT1 (CLEC2D) on prostate cancer cells inhibits NK cell-mediated killing through LLT1-NKRP1A interaction (TUM10P.1052)

Abstract

Abstract Prostate cancer is the most common type of cancer diagnosed and the second leading cause of cancer-related death in American men. Natural Killer (NK) cells are the first line of defense against cancer and infections. In order to establish and grow, cancer cells must escape NK cell-mediated killing. NK cell function is regulated by a delicate balance between signals received through activating and inhibitory receptors. We have identified LLT1 (Lectin-like transcript 1 or CLEC2D) as a counter-receptor for the NK cell inhibitory receptor NKRP1A (CD161). Interaction of LLT1 expressed on target cells with NKRP1A inhibits NK cell activation. Recently, we have found that LLT1 is overexpressed on DU145, LNCaP, and PC3 prostate cancer cells both at the mRNA and protein level. Blocking LLT1 interaction with NKRP1A by anti-LLT1 mAb increased the killing of prostate cancer cells. NK-mediated killing of DU145 in the presence of anti-LLT1 mAb showed the maximum killing. Also, LLT1 was found to be overexpressed in primary prostate cancer tissues, whereas its level of expression was minimal in normal prostate tissue. The results indicate that prostate cancer cells may evade immune attack by NK cells by expressing LLT1 gene to inhibit NK cell-mediated cytolytic activity through LLT1-NKRP1A interaction. Blocking LLT1-NKRP1A interaction will make prostate cancer cells susceptible to killing by NK cells and therefore may be a new therapeutic option for treatment of prostate cancer.