Journal
SCIENTIFIC REPORTS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-017-14970-0
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Funding
- National Institute of Health grant [T32CA090223]
- Pelotonia Postdoctoral Fellowship
- Pelotonia undergraduate fellowship program
- CCSG [P30CA016058]
- National Cancer Institute grant [P01CA095426, P30 CA016058]
- NIH R01 grant [HL114940]
- Donald A Adam Comprehensive Melanoma Research Center at Moffitt Cancer Center
- National Cancer Institute, part of the National Institutes of Health [P50 CA168536]
- Flow Cytometry Core at the H. Lee Moffitt Cancer Center & Research Institute
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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 signal transduction. 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 [H-3]-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.
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