Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet-activating factor
Title | Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet-activating factor |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | 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 DS, Konger RL, Travers JB |
Journal | Cancer Res |
Volume | 74 |
Issue | 23 |
Pagination | 7069-78 |
Date Published | 2014 Dec 1 |
ISSN | 1538-7445 |
Keywords | Animals, Antineoplastic Agents, Antioxidants, Cell Line, Tumor, Cyclooxygenase 2 Inhibitors, Female, Glycerylphosphorylcholine, Humans, Melanoma, Experimental, Mice, Mice, Inbred C57BL, Oxidative Stress, Platelet Activating Factor, Platelet Membrane Glycoproteins, Reactive Oxygen Species, Receptors, G-Protein-Coupled, Signal Transduction, T-Lymphocytes, Regulatory |
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. |
DOI | 10.1158/0008-5472.CAN-14-2043 |
Alternate Journal | Cancer Res. |
PubMed ID | 25304264 |
PubMed Central ID | PMC4252249 |
Grant List | K22ES023850 / ES / NIEHS NIH HHS / United States R01 AG048946 / AG / NIA NIH HHS / United States R01 ES020866 / ES / NIEHS NIH HHS / United States R01 HL062996 / HL / NHLBI NIH HHS / United States R01 HL062996 / HL / NHLBI NIH HHS / United States R01CA134014 / CA / NCI NIH HHS / United States R21 ES020965 / ES / NIEHS NIH HHS / United States U54 HL117798 / HL / NHLBI NIH HHS / United States |