Myeloid derived suppressor cells (MDSC) produce nitric oxide (NO) and inhibit dendritic cell (DC) immune responses in cancer. DCs present cancer cell antigens to CD4 + T cells through Jak-STAT signaltransduction. In this study, NO donors (SNAP and DETA-NONOate) inhibited DC antigen presentation. As expected, MDSC isolated from peripheral blood mononuclear cells (PBMC) from cancer patients produced high NO levels. We hypothesized that NO producing MDSC in tumor-bearing hosts would inhibit DC antigen presentation. Antigen presentation from DCs to CD4 + T cells (T cell receptor transgenic OT-II) was measured via a [ 3 H]-thymidine incorporation proliferation assay. MDSC from melanoma tumor models decreased the levels of proliferation more than pancreatic cancer derived MDSC. T cell proliferation was restored when MDSC were treated with inhibitors of inducible nitric oxide synthase (L-NAME and NCX-4016). A NO donor inhibited OT II T cell receptor recognition of OT II specific tetramers, thus serving as a direct measure of NO inhibition of antigen presentation. Our group has previously demonstrated that STAT1 nitration also mediates MDSC inhibitory effects on immune cells. Therefore, a novel liquid chromatography-tandem mass spectrometry assay demonstrated that nitration of the STAT1-Tyr701 occurs in PBMC derived from both pancreatic cancer and melanoma patients.Melanoma cells are recognized by the immune system, but the anti-tumor activity of T cells and natural killer (NK) cells is inhibited by multiple mechanisms mediated by immune suppressor cells including depletion of nutrients from the tumor microenvironment, production of reactive oxygen and nitrogen species, secretion of immune-suppressive cytokines and induction of additional inhibitory immune cells 1 . Presentation of antigens to T cells by dendritic cells (DCs) is defective in the setting of melanoma 2 . Recently, it has been shown that stimulation of DCs with type I interferons (IFN-α and β) and down-stream signal transduction via the Janus kinase-signal transducer and activator of transcription (Jak-STAT) pathway is critically important to immune surveillance and the generation of effective host T cell immune responses to cancer 3,4 . Furthermore, in dendritic cells, IFN-α signaling is responsible for up-regulation of class I and class II MHC molecules for the presentation of antigens by dendritic cells [5][6][7] . It has been demonstrated that the anti-tumor effects of IFN-α were dependent on STAT1 signal transduction in immune cells via phosphorylation of tyrosine 701 8 . Jak-STAT signaling was markedly inhibited in human peripheral blood immune cells from tumor bearing patients 9 , More recently, we

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