Blockade of tumor necrosis factor alpha signaling in tumor-associated macrophages as a radiosensitizing strategy.
Most cancer patients receive radiotherapy during the course of their disease. Improvements in the therapeutic index have been based mainly on physical improvements in delivery, as radiosensitizer development to target tumor cells has yet to yield effective agents. Recent investigations have focused on the tumor stroma as a target for radiosensitization. Here, we report that depletion of tumor-associated macrophages (TAMvarphi) by systemic or local injection of the macrophage-depleting liposomal clodronate before radiotherapy can increase the antitumor effects of ionizing radiation (IR), either as a large single dose (20 Gy) or as a fractionated dose (2 Gy x 10). Coimplantation of tumor cells with bone marrow-derived macrophages (BMDMvarphi) increased tumor radioresistance. Studies using mice with germline deletions in tumor necrosis factor receptors 1 and 2 (TNFR1,2(-/-)) or TNFalpha (TNF(-/-)), or treatment of wild-type mice with a soluble TNF receptor fusion protein (Enbrel), revealed that radioresistance mediated by BMDMvarphi required intact TNFalpha signaling. Radiation exposure upregulated vascular endothelial growth factor (VEGF) in macrophages and VEGF-neutralizing antibodies enhanced the antitumor response to IR. Thus, the radioprotective effect of TNFalpha was mediated by TAM-produced VEGF. Our findings offer a mechanistic basis to target macrophage populations generally or TNFalpha-induced macrophage VEGF specifically as tractable strategies to improve the efficacy of radiotherapy.
Department of Radiation and Cellular Oncology and Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, Illinois 60637, USA.
Yuru
Y
Meng
Michael A
MA
Beckett
Hua
H
Liang
Helena J
HJ
Mauceri
Nico
N
van Rooijen
Kenneth S
KS
Cohen
Ralph R
RR
Weichselbaum
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004002:Clodronic Acid / Q000008:administration & dosage / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D000068800:Etanercept; D007074:Immunoglobulin G / Q000494:pharmacology*; D008081:Liposomes / Q000008:administration & dosage / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000532:radiotherapy*; D011836:Radiation Tolerance / Q000187:drug effects / Q000235:genetics; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018124:Receptors, Tumor Necrosis Factor; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D007074:Immunoglobulin G; D008081:Liposomes; D011838:Radiation-Sensitizing Agents; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D004002:Clodronic Acid; D000068800:Etanercept