Nitric oxide-producing myeloid-derived suppressor cells inhibit vascular E-selectin expression in human squamous cell carcinomas.
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.
Harvard Skin Disease Research Center and Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Ahmed E
AE
Gehad
Michael K
MK
Lichtman
Chrysalyne D
CD
Schmults
Jessica E
JE
Teague
Adam W
AW
Calarese
Ying
Y
Jiang
Rei
R
Watanabe
Rachael A
RA
Clark
D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D001119:Arginase / Q000235:genetics / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D039521:CD11c Antigen / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020405:Dermis / Q000166:cytology; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006684:HLA-DR Antigens / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D022423:Myeloid Cells / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology
D000945:Antigens, Differentiation, T-Lymphocyte; C515334:CCR2 protein, human; D039481:CD11b Antigen; D039521:CD11c Antigen; C063419:CTAGE1 protein, human; D019040:E-Selectin; D004791:Enzyme Inhibitors; D006684:HLA-DR Antigens; C509295:ITGAM protein, human; D008562:Membrane Glycoproteins; D054390:Receptors, CCR2; D019335:Nitroarginine; D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; C574619:ARG1 protein, human; D001119:Arginase