Highly effective NK cells are associated with good prognosis in patients with metastatic prostate cancer.

Clinical outcome of patients with metastatic prostate cancer (mPC) at diagnosis is heterogeneous and unpredictable; thus alternative treatments such as immunotherapy are investigated. We retrospectively analyzed natural killer (NK) cells by flow cytometry in peripheral blood from 39 mPC patients, with 5 year-follow-up, and their correlation with time to castration resistance (TCR) and overall survival (OS). In parallel, NK functionality was carried out against prostate tumor cell lines, analyzed for the expression of NK cell ligands, to identify the receptors involved in PC recognition. NK cells from patients with longer TCR and OS displayed high expression of activating receptors and high cytotoxicity. The activating receptors NKp30 and NKp46 were the most obvious predictive markers of OS and TCR in a larger cohort of mPC patients (OS: p= 0.0018 and 0.0009; TCR: p= 0.007 and < 0.0001 respectively, log-rank test). Importantly, blocking experiments revealed that NKp46, along with NKG2D and DNAM-1 and, to a lesser extent NKp30, were involved in prostate tumor recognition by NK cells. These results identify NK cells as potential predictive biomarkers to stratify patients who are likely to have longer castration response, and pave the way to explore therapies aimed at enhancing NK cells in mPC patients.