Alterations of natural killer cell receptors as biomarkers associated with the severity of the disease in prostate cancer.

Abstract

e15155 Background: Recently, therapeutic vaccines and monoclonal antibody-based therapies have been investigated as promising new treatments against prostate cancer (PC). Natural killer (NK) cells which have anti-tumoral activity thus represent promising candidates for immunotherapy. Our group have reported major impairments of NK in acute myeloid leukemia and recently in metastatic breast cancer. The aim of this work was to evaluate the phenotype and function of NK cells in patients with localized and metastatic PC to determine their role in disease progression. Methods: Activating and inhibitory receptors were analyzed in peripheral NK cells from 14 patients with localized PC, 33 with metastatic disease and 30 healthy donors. NK function was evaluated by measuring CD107 degranulation. Results: The ratio mean fluorescence intensity RMFI (MFI receptor/MFI control isotype) of the activating receptor NKp30 was significantly lower in patients (7.30 +/- 0.68, p=0.0059) than in HD (10.99 +/- 1.34), whereas NKp46 was lower in the metastatic patients only (11.76 +/- 1.18) compared to the localized cases (21.86 +/- 4.25) and HD (19.13 +/- 2.39). The RMFI of 2B4 (47.14 +/- 7.99), the percentage of positive cells for the inhibitory receptor ILT2 (49.34 +/- 3.90, p=0.0003) and the maturation marker CD57 (41.13 +/- 4.69, p=0.0014) were significantly upregulated in patients compared with HD (2B4 23.09 +/- 4.74, ILT2 20.65 +/- 3.09, CD57 21.36 +/- 3.07), with a more pronounced increase in the metastatic groups. The RMFI of other receptors such as NKG2D or CD94 does not differ. NK cells from patients were significantly less effective (17.90% +/- 1.48, p<0.0001) than NK from HD (30.31% +/- 2.70) to degranulate against the K562 target or prostate tumor cell lines. Conclusions: We observed an altered phenotype of NK cells in PC, correlated with decreased NK cell function, with alterations more pronounced during metastatic progression. Prostate tumor cells could have the ability to impair NK cell visibility through the modulation of their receptors and consequently decrease their cytotoxic function. This highlights the possibility of restoring NK cells cytotoxicity as a future therapy against PC.