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 Tyler, Raymond L. Konger, Jeffrey B. Travers

Research output: Contribution to journalArticle

22 Citations (Scopus)

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
Externally publishedYes

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Platelet Activating Factor
Immunity
Neoplasms
Drug Therapy
Melanoma
Cyclooxygenase 2 Inhibitors
Regulatory T-Lymphocytes
Treatment Failure
Pharmaceutical Preparations
platelet activating factor receptor
Reactive Oxygen Species
Oxidative Stress
Antioxidants
Lipids
Therapeutics
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Sahu, R. P., Ocana, J. A., Harrison, K. A., Ferracini, M., Touloukian, C. E., Al-Hassani, M., ... 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

Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet-activating factor. / 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; Konger, Raymond L.; Travers, Jeffrey B.

In: Cancer Research, Vol. 74, No. 23, 01.12.2014, p. 7069-7078.

Research output: Contribution to journalArticle

Sahu, RP, Ocana, JA, Harrison, KA, Ferracini, M, Touloukian, CE, Al-Hassani, M, Sun, L, Loesch, M, Murphy, RC, Althouse, SK, Perkins, SM, Speicher, PJ, Tyler, D, Konger, RL & Travers, JB 2014, 'Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet-activating factor', Cancer Research, vol. 74, no. 23, pp. 7069-7078. https://doi.org/10.1158/0008-5472.CAN-14-2043
Sahu RP, Ocana JA, Harrison KA, Ferracini M, Touloukian CE, Al-Hassani M et al. Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet-activating factor. Cancer Research. 2014 Dec 1;74(23):7069-7078. https://doi.org/10.1158/0008-5472.CAN-14-2043
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 ; Konger, Raymond L. ; Travers, Jeffrey B. / Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet-activating factor. In: Cancer Research. 2014 ; Vol. 74, No. 23. pp. 7069-7078.
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