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

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

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22 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)7069-7078
Number of pages10
JournalCancer Research
Volume74
Issue number23
DOIs
StatePublished - Dec 1 2014

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Sahu, R. P., Ocana, J. A., Harrison, K. A., Ferracini, M., Touloukian, C. E., Al-Hassani, M., Sun, L., Loesch, M., Murphy, R. C., Althouse, S. K., Perkins, S. M., Speicher, P. J., Tyler, D. S., Konger, R. L., & Travers, J. B. (2014). Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet-activating factor. Cancer Research, 74(23), 7069-7078. https://doi.org/10.1158/0008-5472.CAN-14-2043