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[Cancer Research 61, 7240-7247, October 1, 2001]
© 2001 American Association for Cancer Research

Immunology

Macrophages Orchestrate the Immune Response to Tumor Cell Death1

Michael J. Gough, Alan A. Melcher, Atique Ahmed, Marka R. Crittenden, David S. Riddle, Emmanouela Linardakis, Anja N. Ruchatz, Lisa M. Emiliusen and Richard G. Vile2

Molecular Medicine Program, Mayo Clinic, Rochester, Minnesota 55905 [M. J. G., A. A., M. R. C., D. S. R., E. L., A. N. R., L. M. E., R. G. V.], and ICRF Oncology Unit, St. James University Hospital, Leeds LS9 7TF, United Kingdom [A. A. M.]

The mechanisms by which the immune system distinguishes normal developmental cell death from pathological immunogenic cell killing are central to effective cancer immunotherapy. Using HSVtk suicide gene therapy, we showed that macrophages can distinguish between tumor cells dying through classical apoptosis and tumor cells engineered to die through nonapoptotic mechanisms, resulting in secretion of either immunosuppressive cytokines (interleukin 10 and transforming growth factor ß) or inflammatory cytokines (tumor necrosis factor {alpha} or interleukin 1ß), respectively. Additionally heat shock protein 70 acts as one component of a bimodal alarm signal that activates macrophages in the presence of stressful, immunogenic tumor cell killing. These differential responses of macrophages can also be used to vaccinate mice against tumor challenge, using adoptive transfer, as well as to cure mice of established tumors.




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Copyright © 2001 by the American Association for Cancer Research.