Abstract 3656: MDSC-generated nitric oxide leads to an impairment of NK cell functions in metastatic melanoma patients

Abstract

Abstract Myeloid-derived suppressor cells (MDSCs) are able to inhibit the function of immune cells within the tumor microenvironment. The interaction of MDSCs with T cells has been studied extensively. However, the interaction of MDSCs with innate immune cells such as NK cells is not well understood. This study investigated whether the presence of MDSCs could impair the function of NK cells. MDSC (CD33+HLA-DRneg/lowCD11b+) and autologous NK cells (CD56+CD3neg) were isolated from the peripheral blood of metastatic melanoma patients and co-cultured overnight at a 1:1 ratio (2 x 105 cells each). Culture with MDSC led to a 70% decrease in NK cell mediated antibody dependent cellular cytotoxicity (ADCC) against HER2+ SkBr3 cells coated with an anti-HER2 antibody and a two-fold decrease in the production of interferon-gamma in response to these targets. Stimulation of the NK cell Fc receptor by immobilized immunoglobulin G (IgG) led to phosphorylation of Erk (p-Erk) and this event was significantly inhibited in the presence of MDSC in a dose and contact-dependent manner (p<0.05). Co-culture of NK cells with MDSC also led to reduced expression of the NKp30 activating receptor (1.7-fold decrease) and a decrease in cytotoxicity against the K562 cell line. MDSC were able to generate significant levels of nitric oxide (NO) and inhibition of MDSC NO synthesis in co-cultures led to a significant improvement in NK cell cytotoxicity and cytokine production (p<0.05). Depletion of MDSC from BALB/c mice bearing tumors of the CT26 adenocarcinoma cell line led to a three-fold increase in NK cell mediated ADCC. These results demonstrate that MDSC-derived NO can inhibit NK cell function, and suggest that strategies aimed at eliminating or deactivating MDSC may lead to enhanced efficacy of immune based therapies. Citation Format: Prashant Trikha, Bethany Mundy-Bosse, Ian Landi, Elizabeth McMichael, Amanda Harper, Megan Duggan, Nancy Stasik, Kari Kendra, Thomas Olencki, William Carson. MDSC-generated nitric oxide leads to an impairment of NK cell functions in metastatic melanoma patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3656. doi:10.1158/1538-7445.AM2014-3656