[Show abstract][Hide abstract] ABSTRACT: Squamous cell carcinomas (SCCs) are sun-induced skin cancers that are particularly numerous and aggressive in immunosuppressed individuals. SCCs evade immune detection at least in part by downregulating E-selectin on tumor vessels, thereby restricting entry of skin-homing T cells into tumors. We find that nitric oxide (NO) potently suppresses E-selectin expression on human endothelial cells and that SCCs are infiltrated by NO-producing iNOS(+) CD11b(+) CD33(+) CD11c(-) HLA-DR(-) myeloid-derived suppressor cells (MDSCs). MDSCs from SCCs produced NO, transforming growth factor-β (TGF-β), and arginase, and inhibited endothelial E-selectin expression in vitro. MDSCs from SCCs expressed the chemokine receptor CCR2 (chemokine (C-C motif) receptor 2) and tumors expressed the CCR2 ligand human β-defensin 3 (HBD3), suggesting that CCR2/HBD3 interactions may contribute to MDSC recruitment to SCCs. Treatment of SCCs in vitro with the inducible nitric oxide synthase (iNOS) inhibitor N(ω)-nitro-L-arginine(L-NNA) induced E-selectin expression at levels comparable to imiquimod-treated SCCs undergoing immunologic destruction. Our results suggest that local production of NO in SCCs may impair vascular E-selectin expression. We show that MDSCs are critical producers of NO in SCCs and that NO inhibition restores vascular E-selectin expression, potentially enhancing T-cell recruitment. The iNOS inhibitors and other therapies that reduce NO production may therefore be effective in the treatment of SCCs and their premalignant precursor lesions, actinic keratoses.