title: Δ9-Tetrahydrocannabinol-mediated epigenetic modifications elicit myeloid-derived suppressor cell activation via STAT3/S100A8.
abstract: MDSCs are potent immunosuppressive cells that are induced during inflammatory responses, as well as by cancers, to evade the anti-tumor immunity. We recently demonstrated that marijuana cannabinoids are potent inducers of MDSCs. In the current study, we investigated the epigenetic mechanisms through which THC, an exogenous cannabinoid, induces MDSCs and compared such MDSCs with the naïve MDSCs found in BM of BL6 (WT) mice. Administration of THC into WT mice caused increased methylation at the promoter region of DNMT3a and DNMT3b in THC-induced MDSCs, which correlated with reduced expression of DNMT3a and DNMT3b. Furthermore, promoter region methylation was decreased at Arg1 and STAT3 in THC-induced MDSCs, and consequently, such MDSCs expressed higher levels of Arg1 and STAT3. In addition, THC-induced MDSCs secreted elevated levels of S100A8, a calcium-binding protein associated with accumulation of MDSCs in cancer models. Neutralization of S100A8 by use of anti-S100A8 (8H150) in vivo reduced the ability of THC to trigger MDSCs. Interestingly, the elevated S100A8 expression also promoted the suppressive function of MDSCs. Together, the current study demonstrates that THC mediates epigenetic changes to promote MDSC differentiation and function and that S100A8 plays a critical role in this process.
authors.affiliation: *Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, USA; and WJB Dorn Veterans Affairs Medical Center, Columbia, South Carolina, USA.
authors.forename: Jessica Margaret
authors.initials: JM
authors.lastname: Sido
authors.affiliation: *Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, USA; and WJB Dorn Veterans Affairs Medical Center, Columbia, South Carolina, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Yang
authors.affiliation: *Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, USA; and WJB Dorn Veterans Affairs Medical Center, Columbia, South Carolina, USA.
authors.forename: Prakash S
authors.initials: PS
authors.lastname: Nagarkatti
authors.affiliation: *Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, USA; and WJB Dorn Veterans Affairs Medical Center, Columbia, South Carolina, USA mitzi.nagarkatti@uscmed.sc.edu.
authors.forename: Mitzi
authors.initials: M
authors.lastname: Nagarkatti
mesh_terms: D000818:Animals; D001119:Arginase / Q000096:biosynthesis / Q000235:genetics; D040501:Calgranulin A / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D000090205:DNA Methyltransferase 3A; D013759:Dronabinol; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007108:Immune Tolerance / Q000187:drug effects*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology*; D011401:Promoter Regions, Genetic / Q000187:drug effects* / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D013047:Specific Pathogen-Free Organisms; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D000097584:DNA Methyltransferase 3B
chemical_list: D001119:Arginase; D040501:Calgranulin A; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D013759:Dronabinol; D050796:STAT3 Transcription Factor; D000097584:DNA Methyltransferase 3B; C000715535:Dnmt3a protein, mouse; C086145:S100a8 protein, mouse; C494087:Stat3 protein, mouse; C544448:Arg1 protein, mouse
keywords: DNA methylation; T cell suppression; arginase 1; cannabinoid