title: Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet-activating factor.
abstract: Oxidative stress suppresses host immunity by generating oxidized lipid agonists of the platelet-activating factor receptor (PAF-R). Because many classical chemotherapeutic drugs induce reactive oxygen species (ROS), we investigated whether these drugs might subvert host immunity by activating PAF-R. Here, we show that PAF-R agonists are produced in melanoma cells by chemotherapy that is administered in vitro, in vivo, or in human subjects. Structural characterization of the PAF-R agonists induced revealed multiple oxidized glycerophosphocholines that are generated nonenzymatically. In a murine model of melanoma, chemotherapeutic administration could augment tumor growth by a PAF-R-dependent process that could be blocked by treatment with antioxidants or COX-2 inhibitors or by depletion of regulatory T cells. Our findings reveal how PAF-R agonists induced by chemotherapy treatment can promote treatment failure. Furthermore, they offer new insights into how to improve the efficacy of chemotherapy by blocking its heretofore unknown impact on PAF-R activation.
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Ravi P
authors.initials: RP
authors.lastname: Sahu
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana. Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Jesus A
authors.initials: JA
authors.lastname: Ocana
authors.affiliation: Department of Pharmacology, University of Colorado Health Sciences Center, Aurora, Colorado.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Harrison
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Matheus
authors.initials: M
authors.lastname: Ferracini
authors.affiliation: Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Touloukian
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Hassani
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Louis
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Mathew
authors.initials: M
authors.lastname: Loesch
authors.affiliation: Department of Pharmacology, University of Colorado Health Sciences Center, Aurora, Colorado.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Murphy
authors.affiliation: Department of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Sandra K
authors.initials: SK
authors.lastname: Althouse
authors.affiliation: Department of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Perkins
authors.affiliation: The Department of Surgery, Duke University Medical Center, Durham, North Carolina.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Speicher
authors.affiliation: The Department of Surgery, Duke University Medical Center, Durham, North Carolina.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Tyler
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Konger
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana. Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana. The Richard L. Roudebush V.A. Medical Center, Indianapolis, Indiana. jtravers@iupui.edu.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Travers
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology* / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D045744:Cell Line, Tumor; D052246:Cyclooxygenase 2 Inhibitors / Q000276:immunology / Q000494:pharmacology; D005260:Female; D005997:Glycerylphosphorylcholine / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects / Q000276:immunology; D010972:Platelet Activating Factor / Q000819:agonists* / Q000276:immunology / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D052246:Cyclooxygenase 2 Inhibitors; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D017382:Reactive Oxygen Species; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D005997:Glycerylphosphorylcholine