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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2014-12, Vol.74 (23), p.7069-7078
• Main Authors: Sahu, Ravi P, Ocana, Jesus A, Harrison, Kathleen A, Ferracini, Matheus, Touloukian, Christopher E, Al-Hassani, Mohammed, Sun, Louis, Loesch, Mathew, Murphy, Robert C, Althouse, Sandra K, Perkins, Susan M, Speicher, Paul J, Tyler, Douglas S, Konger, Raymond L, Travers, Jeffrey B
• Format: Article
• Language: English
• Subjects: 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
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-14-2043

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.