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: Ravi P Sahu, Jesus A Ocana, Kathleen A Harrison, Matheus Ferracini, Christopher E Touloukian, Mohammed Al-Hassani, Louis Sun, Mathew Loesch, Robert C Murphy, Sandra K Althouse, Susan M Perkins, Paul J Speicher, Douglas S Tyler, Raymond L Konger, Jeffrey B Travers
• Journal: Cancer research (Cancer Res) Vol. 74 Issue 23 Pg. 7069-78 (Dec 01 2014) ISSN: 1538-7445 [Electronic] United States
• PMID: 25304264 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

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

Topics

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