Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet-activating factor

Cancer Res. 2014 Dec 1;74(23):7069-78. doi: 10.1158/0008-5472.CAN-14-2043. Epub 2014 Oct 10.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / immunology*
  • Antineoplastic Agents / pharmacology*
  • Antioxidants / pharmacology
  • Cell Line, Tumor
  • Cyclooxygenase 2 Inhibitors / immunology
  • Cyclooxygenase 2 Inhibitors / pharmacology
  • Female
  • Glycerylphosphorylcholine / immunology
  • Glycerylphosphorylcholine / metabolism
  • Humans
  • Melanoma, Experimental / drug therapy*
  • Melanoma, Experimental / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Oxidative Stress / drug effects
  • Oxidative Stress / immunology
  • Platelet Activating Factor / agonists*
  • Platelet Activating Factor / immunology
  • Platelet Activating Factor / metabolism
  • Platelet Membrane Glycoproteins / immunology
  • Platelet Membrane Glycoproteins / metabolism
  • Reactive Oxygen Species / immunology
  • Reactive Oxygen Species / metabolism
  • Receptors, G-Protein-Coupled / immunology
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology


  • Antineoplastic Agents
  • Antioxidants
  • Cyclooxygenase 2 Inhibitors
  • Platelet Activating Factor
  • Platelet Membrane Glycoproteins
  • Reactive Oxygen Species
  • Receptors, G-Protein-Coupled
  • platelet activating factor receptor
  • Glycerylphosphorylcholine